Substituted bicyclic pyrimidines

ABSTRACT

The present invention is related to chemical compositions, processes for the preparation thereof and uses of the composition. Particularly, the present invention relates to compositions that include substituted heterobicyclic pyrimidines of Formula (I): 
                         
wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, W, and ring A are as defined herein; pharmaceutical compositions of substituted heterobicyclic pyrimidines of Formula (I); and their use in the treatment of chronic neurodegenerative diseases, neurotraumatic diseases, depression and/or diabetes. More particularly, the present invention relates to substituted pyrazolopyrimidines of Formula (I).

This application is a divisional application of U.S. application Ser.No. 11/803,320, filed May 14, 2007, which, in turn, claims the benefit,under 35 USC 119(e) to U.S. Provisional Application 60/800,375, filedMay 15, 2006.

FIELD OF THE INVENTION

The present invention is related to chemical compositions, processes forthe preparation thereof and uses of the composition. Particularly, thepresent invention relates to compositions that include substitutedheterobicyclic pyrimidines of Formula (I):

wherein R¹, R², R³, R⁴, R⁵, X, W, and ring A are as defined herein;pharmaceutical compositions of substituted heterobicyclic pyrimidines ofFormula (I); and their use in the treatment of chronic neurodegenerativediseases, neurotraumatic diseases, depression and/or diabetes. Moreparticularly, the present invention relates to substitutedpyrazolopyrimidines of Formula (I).

BACKGROUND OF THE INVENTION

This invention relates to novel substituted heterobicyclic pyrimidinecompounds, in particular substituted pyrazolopyrimidine oxindoles, thatact as inhibitors of glycogen synthase kinase 3 and cyclin dependantkinase 5.

Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinasecomposed of two isoforms (α and β) encoded by different genes. GSK3 ishighly expressed in the central and peripheral nervous system, withGSK3β predominating in the brain. Both isoforms of GSK3 phosphorylateand regulate the activity of several protein substrates, includingglycogen synthase, β-catenin, pyruvate dehydrogenase, elongationinitiation factor 2b, and tau. GSK3 is regulated by insulin, whichstimulates glycogen synthesis via receptor activation of PI3 kinase andprotein kinase B. PKB phosphorylates GSK3β on serine 9, resulting in itsinactivation. Insulin also activates protein phosphatase 1. Both ofthese actions of insulin lead to dephosphorylation and activation ofglycogen synthase (Srivastava and Pandey, Mol Cell Biochem. 182:135-141,1998; Cohen, Biochem Soc Trans., 21:555-567, 1993), and production ofglycogen from glucose. β-catenin degradation is increased followingphosphorylation by GSK3 (Ikeda, et al., EMBO, 17:1371-1384, 1998). Thereduction in available β-catenin may increase the sensitivity of neuronsto amyloid β (Aβ) toxicity (Zhang, et al., Nature, 395:698-702, 1998).GSK3β also phosphorylates pyruvate dehydrogenase and prevents theconversion of pyruvate to acetyl CoA (Hoshi, et al., PNAS, 93:2719-2723,1996). This acetyl CoA is critical for the synthesis of acetylcholine,the loss of which is implicated in the cognitive decline in Alzheimer'sDisease (AD). GSK3α regulates production of Aβ from the amyloidprecursor protein (Phiel, et al., Nature. 423:435-9, 2003). Twoproteases, β- and γ-secreatase liberate the amino and carboxy terminus(respectively) of Aβ. In a concentration dependant manner, Aβprecipitates into toxic, fibrillary species in the AD brain and isthought to lead to additional sequalae of the disease. Phosphorylationof eIF2B by GSK-3β reduces protein translation. eIF2B activation by IGF1is mediated by the inactivation of GSK3β (Welsh, et al., FEBS Letts,421:125-130, 1997). The role of tau phosphorylation by GSK3 will bediscussed following description of CDK5.

Cyclin Dependant Kinase 5 (CDK5) is also a serine/threonine proteinkinase, and is structurally related to GSK3. CDK5 activationpredominates in the nervous system due to expression of p35, anaccessory protein related to cyclins and necessary for CDK5 activity(Dhavan and Tsai, Nat Rev Mol Cell Biol, 2:749-759, 2001). Unlike CDK1,2, 4, and 6 which are active in the cell cycle, CDK5 is activated inneurons after cell division has ended, following differentiation andexpression of p35. CDK5 activity is regulated by expression of p35 and acalpain-cleaved form of p35, known as p25 (Patzke and Tsai, J Biol Chem,277:8054-8060, 2002). The generation of p25 leads to increased andmislocalized CDK5 activity since 1) p25 is missing the membranelocalizing portion found in p35, and 2) p25 has a longer resident halflife in the cytoplasm. CDK5 phosphorylates a number of substratesincluding DARPP-32, NR2a (NMDA receptor subunit), MEF-2, PSD-95,synaptojanin-1, CRMP2, and tau. DARPP-32 phosphorylation by CDK5 atthr75 leads to the inhibition of PKA in the dopamine 1 receptor (D1)signaling cascade, thereby inhibiting D1 signaling (Bibb, et al.,Nature, 402:669-671 1997). Facilitation of D1 signaling may be usefulfor the treatment of depression or Parkinson's Disease (Chergui, et al.,PNAS, 10:2191-2196, 2004). NR2a phosphorylation by CDK5 modulates longterm potentiation and may induce apoptotic cell death following ischemia(Wang, et al., Nat. Neurosci., 6:1039-47, 2003). CDK5-dependentphosphorylation of PSD-95 dynamically regulates the clustering ofPSD-95/NMDA receptors at synapses, providing a possible mechanism forrapid changes in density and/or number of synaptic receptors (Morabito,et. al., J. Neurosci., 24:865-876, 2004). CDK5 also phosphorylates thepresynaptic phosphatase synaptojanin 1 and regulates its function bothin vitro and in intact synaptosomes (Lee, et. al., PNAS, 101:546-551,2004). CRMP2 is also phosphorylated by CDK5, leading to a reduction inCRMP-tubulin binding affinity and modulating growth cone collapse. CDK5primarily phosphorylates CRMP2 at Ser522 and GSK3β secondarilyphosphorylates at Thr509. Dual-phosphorylated CRMP2 is recognized withthe antibody 3F4, highly reactive with the neurofibrillary tangles (NFT)of AD brain (Uchida, et al., Genes Cells, 10:165-179, 2005). Overall,the role of CDK5 in synaptic formation and function is wellsubstantiated.

Experimental evidence supports a role for both GSK3 and CDK5 in thetangle and plaque pathology of AD, namely in the tauhyperphosphorylation that leads to NFT formation. AD brain ischaracterized by intracellular NFTs and extracellular senile plaquesconsisting of Aβ deposits. Both of these protein aggregates are thoughtto precipitate the neuronal and synaptic loss, leading to the memoryloss and cognitive decline of AD (Hardy, J Mol Neurosci, 20:203-6,2003).

NFTs are composed of hyperphosphorylated, aggregated forms of the neuronspecific, cytoskeletal protein tau (Cairns, et. al., J Pathol,204:438-449, 2004). The primary function of tau is to stabilize neuronalmicrotubules, to maintain axonal architecture, and to allow transport ofmaterials both from the cell body to the synapse, and from the synapseback to the cell body. In AD, tau is hyperphosphorylated at manyserine/threonine residues, leading to poor binding of tau to themicrotubule and loss of trophic interplay between the cell body and thesynapse. NFTs represent one of the characteristic features of the ADbrain, and are also present in the brains of individuals withprogressive supranuclear palsy, frontotemporal dementia withparkinsonism-17, Neimann-Pick's disease, corticobasal degeneration,amyotrophic lateral sclerosis, dementia puglistica, etc.

NFTs are composed of insoluble aggregates of tau protein,hyperphosphorylated on many serine and threonine residues and formedinto paired helical filaments. The hyperphosphorylation of tau resultsin a lower affinity for the microtubule and may represent the first steptoward aggregate formation. Both CDK5 and GSK3 phosphorylate tau in bothcell-free and cell-based in vitro systems at many of the same sitespresent in the AD brain. Antibodies directed against both GSK3 (Pei, et.al., J. Neuropath. Exp. Neurol., 58:1010-1019, 1999) and CDK5 (Pei, et.al., Brain Res, 797:267-277, 1998) decorate the NFTs in the AD brain,demonstrating the close association between these kinases and thehyperphosphorylated tau that comprises the tangles. Overexpression ofeither kinase activity in transgenic animal models (Lucas, et al., EMBOJ., 20:27-39, 2001; Cruz, et al., Neuron, 40:471-83, 2003) alsodemonstrates their ability to hyperphosphorylate tau (both CDK5 andGSK3) and cause the formation of mature NFTs and neuronal loss (CDK5).Phosphorylation by GSK3 at many epitopes requires prior phosphorylationby a so called “priming” kinase C-terminal to the GSK3 phosphorylationsite (Cohen and Goedert, Nat Rev Drug Discov, 3:479-487, 2004).Interestingly, CDK5 has been implicated as a priming kinase (atphosphoserine 235) for GSK3, which acts to phosphorylate threonine 231,a site that is phosphorylated early in the progression of AD NFTpathology (Augustinack, et. al., Acta Neuropathol (Berl). 103:26-35,2002; Li T, Hawkes C, Qureshi H Y, Kar S, Paudel H K, Biochemistry,45:3145-4154, 2006).

Other disease states in which GSK3 is thought to play a role includecerebral ischemia. GSK3 activity is increased in cellular and animalmodels of both neurodegeneration and apoptosis, such as cerebralischemia (Bhat, et al., PNAS, 97:11074-11079, 2000). Lithium, as arepresentative GSK3 inhibitor, is neuroprotective in these models (Ren,et al., PNAS, USA, 100:6210-6215, 2003). Lithium inhibits GSK3 atconcentrations also known to be therapeutic in bipolar disorder (Gould,et al., J Clin Psychiatry, 65:10-21, 2004), implicating GSK3 inhibitionas a therapeutic avenue in this disease.

GSK3 activity is increased in peripheral lymphocytes and brains ofpatients with schizophrenia, as evidenced by reduced levels of both theupstream inhibiting kinase AKT1, and the inhibitory ser9 phosphorylationof GSK3β (Emamian, et al., Nat Genet, 36:131-137, 2004) Clinicaltreatment leads to normalization of this pathway.

Diabetes mellitus type 2 is characterized by reduced insulin productiondue to loss of pancreatic beta cells following a period of reducedinsulin sensitivity. With the insulin receptor signaling dysfunctionthat is also present in the disease, direct inhibition of GSK3 has beenhypothesized to relieve the hyperglycemia and allow for normal glycogensynthesis and glucose utilization (Wagman, et al., Curr Pharm Des.,10:1105-1137, 2004).

These compounds as GSK3 inhibitors are indicated to be useful for thetreatment and/or prophylaxis of conditions in which there is a need forinhibition of GSK3, such as diabetes, conditions associated withdiabetes, chronic neurodegenerative diseases such as Alzheimer'sDisease, Parkinson's Disease, progressive supranuclear palsy, subacutepanencephalitic parkinsonism, postencephalitic parkinsonism, dementiapuglistica, guan parkinsonial dementia complex, Pick's disease,corticobasal degeneration, frontotemporal dementia with parkinsonism,Huntington's disease, AIDS associated dementia, amyotrophic lateralsclerosis, multiple sclerosis, and neurotraumatic diseases such as acutestroke, mood disorders such as schizophrenia and bipolar disorders,promotion of functional recovery post stroke, cerebral bleeding(solitary cerebral amyloid angiopathy), hair loss, obesity,atherosclerotic cardiovascular disease, hypertension, polycystic ovarysyndrome, syndrome X, ischemia, traumatic brain injury, cancer,leukopenia, Down's syndrome, Lewy body disease, inflammation andimmunodeficiency.

These compounds as CDK5 inhibitors are indicated to be useful for thetreatment and/or prophylaxis of conditions in which there is a need forinhibition of CDK5 such as the chronic neurodegenerative diseasesAlzheimer's disease, Parkinson's Disease, progressive supranuclearpalsy, subacute panencephalitic parkinsonism, postencephaliticparkinsonism, dementia puglistica, guan-parkinsonial dementia complex,Pick's disease, corticobasal degeneration, frontotemporal dementia withparkinsonism, Huntington's disease, AIDS-associated dementia,amyotrophic lateral sclerosis and mood disorders such as depression.

Thus, there is a need for novel classes of compounds that possess thebeneficial properties. It has been discovered that a class of compounds,referred to herein as substituted heterobicyclic pyrimidine compounds,in particular substituted pyrazolopyrimidine oxindoles, are useful asagents for treating or preventing various diseases or disordersdisclosed herein.

SUMMARY OF THE INVENTION

The present invention in one aspect is directed to various novelcompounds of structure:

wherein R¹, R², R³, R⁴, R⁵, X and ring A are as defined herein; and itsstereoisomeric forms, mixtures of stereoisomeric forms, tautomericforms, or pharmaceutically acceptable salt forms thereof, wherein theconstituent members are defined infra.

Another object of the present invention is to provide pharmaceuticalcompositions comprising the compounds of the present invention whereinthe compositions comprise one or more pharmaceutically acceptableexcipients and a therapeutically effective amount of at least one of thecompounds of the present invention, or a pharmaceutically acceptablesalt or ester form thereof.

Another object of the present invention is to provide methods oftreating or preventing diseases or disorders, including chronicneurodegenerative diseases is selected from Alzheimer's Disease,Parkinson's Disease, progressive supranuclear palsy, subacutepanencephalitic parkinsonism, postencephalitic parkinsonism, dementiapuglistica, guan-parkinsonial dementia complex, Pick's disease,corticobasal degeneration, frontotemporal dementia with parkinsonism,Huntington's disease, AIDS associated dementia, amyotrophic lateralsclerosis, and multiple sclerosis.

Another object of the present invention is to provide methods oftreating or preventing diseases or disorders, including neurotraumaticdisease selected from acute stroke, mood disorders such as schizophreniaand bipolar disorders, promotion of functional recovery post stroke,cerebral bleeding (solitary cerebral amyloid angiopathy), hair loss,obesity, atherosclerotic cardiovascular disease, hypertension,polycystic ovary syndrome, syndrome X, ischemia, traumatic brain injury,cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation andimmunodeficiency.

Another object of the present invention is to provide methods oftreating depression.

Another object of the present invention is to provide methods oftreating diabetes.

These and other objects, features and advantages of the substitutedpyrazolopyrimidines will be disclosed in the following detaileddescription of the patent disclosure.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment, the present invention provides novel compounds ofFormula (I):

-   and stereoisomeric forms, mixtures of stereoisomeric forms,    tautomeric forms, prodrugs, or pharmaceutically acceptable salt    forms thereof, wherein:-   W is CH or N;-   ring A is

-   R¹, R², R³, and R⁴ at each occurrence are independently selected    from H, halo, —OR¹¹, —NO₂, —CN, —CF₃, —CHF₂, C₂-C₄ alkenyl, C₂-C₄    alkynyl, C₁-C₄ haloalkyl, —NR¹³R¹⁴, —NHOR^(13a), —C(═O)R¹⁵,    —C(═O)OR¹⁵, —OC(═O)R¹⁵, —C(═O)NR¹³R¹⁴, —NR^(13a)C(═O)R¹⁵,    —NR^(13a)CO₂R¹⁵, —OC(═O)NR¹³R¹⁴, —NR^(13a)C(═S)R¹⁵, —SR¹⁵,    —S(═O)R¹⁵, —S(═O)₂R¹⁵, —S(═O)₂NR¹³R¹⁴, and C₁-C₄ alkyl substituted    with 0-1 R¹⁹;-   R⁵ is H, C₁-C₆ alkyl or a prodrug of an amino group;-   R⁶ is selected from H;    -   C₁-C₆ alkyl substituted by 0-2 R²²;    -   C₂-C₆ alkenyl substituted by 0-2 R²²;    -   C₂-C₆ alkynyl substituted by 0-2 R²²; and    -   C₃-C₇ cycloalkyl substituted by 0-3 R²²;-   R⁷ is H, —NO₂, halo, C₁-C₄ alkyl or —NR²³R²⁴;-   X is selected from H, —NR⁹R¹⁰, halo, OR¹², —NO₂, —CN, —CF₃, —CHF₂,    C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ haloalkyl,    —CH₂NR⁹R¹⁰, —CH₂OR¹², —NHOR¹⁶, —C(═O)R¹⁸, —C(═O)OR¹⁸, —OC(═O)R¹⁸,    —C(═O)NR⁹R¹⁰, —NR¹⁶C(═O)R¹⁸, —NR¹⁶CO₂R¹⁸, —OC(═O)NR⁹R¹⁰,    —NR¹⁶C(═S)R¹⁸, —SR¹⁸, —S(═O)R¹⁸, —S(═O)₂R¹⁸, —S(═O)₂NR⁹R¹⁰, and    —NR¹⁶S(═O)₂R¹⁸;-   R⁹ and R¹⁰ at each occurrence are each independently selected from    H, —NH₂;    -   C₁-C₆ alkyl substituted by 0-1 R¹⁹;    -   C₂-C₆ alkenyl substituted by 0-1 R¹⁹;    -   C₂-C₆ alkynyl substituted by 0-1 R¹⁹;    -   C₆-C₁₀ aryl substituted by 0-5 R¹⁹;    -   C₃-C₇ carbocyclyl substituted by 0-5 R¹⁹; and    -   5 to 14 membered heterocyclyl group substituted by 0-5 R¹⁹,        wherein said heterocyclyl group comprises one, two, or three        heteroatoms selected from N, O, and S;    -   5 to 14 membered heteroaryl group substituted by 0-5 R¹⁹,        wherein said heteroaryl group comprises one, two, or three        heteroatoms selected from N, O, and S;-   alternatively, R⁹ and R¹⁰, together with the nitrogen to which they    are attached, form a 3-7 membered heterocyclic ring, wherein said    3-7 membered heterocyclic ring contains a nitrogen atom and    optionally a second atom selected from N, O, S, S(═O), and S(═O)₂,    wherein said 3-7 membered heterocyclic ring is substituted with 0-1    R¹⁷;-   R¹¹ at each occurrence is independently selected from H, C₁-C₄    alkyl, and C₁-C₄ haloalkyl;-   R¹² at each occurrence is independently selected from H, C₁-C₄    haloalkyl and C₁-C₄ alkyl substituted with 0-1 R¹⁹;-   R¹³ and R¹⁴, at each occurrence, are independently selected from H,    C₁-C₄ alkyl substituted with 0-3 R³⁰; and C₆-C₁₀ aryl substituted    with 0-5 R³⁰;-   R^(13a) at each occurrence is independently selected from H, C₁-C₄    alkyl, and C₆-C₁₀ aryl;-   R¹⁵ at each occurrence is independently selected from H,    -   C₁-C₆ alkyl substituted by 0-1 R³⁰;    -   C₂-C₆ alkenyl substituted by 0-1 R³⁰;    -   C₂-C₆ alkynyl substituted by 0-1 R³⁰;    -   C₆-C₁₀ aryl substituted by 0-5 R³⁰;    -   C₃-C₇ carbocyclyl substituted by 0-5 R³⁰; and    -   5 to 14 membered heterocyclyl group substituted by 0-5 R³⁰,        wherein said heterocyclyl group comprises one, two, or three        heteroatoms selected from N, O, and S;    -   5 to 14 membered heteroaryl group substituted by 0-5 R³⁰,        wherein said heteroaryl group comprises one, two, or three        heteroatoms selected from N, O, and S;-   R¹⁶ at each occurrence is independently selected from H and C₁-C₄    alkyl;-   R¹⁷ is H, —NR²³R²⁴, halo, —NO₂, —CN, —CF₃, C₁-C₄ haloalkyl, —NHOH,    OR²⁵, C(═O)R²⁵, C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴,    NR^(23a)C(═O)R²⁵, NR^(23a)CO₂R²⁵, OC(═O)NR²³R²⁴, NR^(23a)C(═S)R²⁵,    SR²⁵, S(═O)R²⁵, S(═O)₂R²⁵; S(═O)₂NR²³R²⁴, —NR^(23a)S(═O)₂R²⁵, or    C₁-C₄ alkyl substituted by 0-1 R¹⁹;-   R¹⁸ at each occurrence is independently selected from H;    -   C₁-C₆ alkyl substituted by 0-1 R³⁰;    -   C₂-C₆ alkenyl substituted by 0-1 R³⁰;    -   C₂-C₆ alkynyl substituted by 0-1 R³⁰;    -   C₆-C₁₀ aryl substituted by 0-5 R³⁰;    -   C₃-C₇ carbocyclyl substituted by 0-5 R³⁰; and    -   5 to 14 membered heterocyclyl group substituted by 0-5 R³⁰,        wherein said heterocyclyl group comprises one, two, or three        heteroatoms selected from N, O, and S;    -   5 to 14 membered heteroaryl group substituted by 0-5 R³⁰,        wherein said heteroaryl group comprises one, two, or three        heteroatoms selected from N, O, and S;-   R¹⁹ at each occurrence is independently selected from H, —NR²³R²⁴,    halo, —NO₂, —CN, —CF₃, C₁-C₄ haloalkyl, —NHOH, OR²⁵, C(═O)R²⁵,    C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴, NR^(23a)C(═O)R²⁵,    NR^(23a)CO₂R²⁵, OC(═O)NR²³R²⁴, NR^(23a)C(═S)R²⁵, SR²⁵, S(═O)R²⁵,    S(═O)₂R²⁵; S(═O)₂NR²³R²⁴, —NR    -   C₁-C₄ alkyl substituted by 0-1 R³⁰;    -   C₂-C₄ alkenyl substituted by 0-1 R³⁰;    -   C₂-C₄ alkynyl substituted by 0-1 R³⁰;    -   C₆-C₁₀ aryl substituted by 0-5 R³⁰;    -   C₃-C₇ carbocyclyl substituted by 0-5 R³⁰; and    -   5 to 14 membered heterocyclyl group substituted by 0-5 R³⁰,        wherein said heterocyclyl group comprises one, two, or three        heteroatoms selected from N, O, and S;    -   5 to 14 membered heteroaryl group substituted by 0-5 R³⁰,        wherein said heteroaryl group comprises one, two, or three        heteroatoms selected from N, O, and S;-   R²² is H, —NR²³R²⁴, —N₃, halo, —NO₂, —CN, —CF₃, C₁-C₄ alkyl, C₂-C₄    alkenyl, C₂-C₄ alkynyl, C₁-C₄ haloalkyl, C₃-C₇ carbocyclyl, phenyl,    —NHOH, OR²⁵, —CH₂OR²⁵, C(═O)R²⁵, C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴,    NR^(23a)C(═O)R²⁵, NR^(23a)CO₂R²⁵, OC(═O)NR²³R²⁴, NR^(23a)C(═S)R²⁵,    SR²⁵, S(═O)R²⁵, S(═O)₂R²⁵; S(═O)₂NR²³R²⁴, or —NR^(23a)S(═O)₂R²⁵;-   R²³ and R²⁴ at each occurrence are each independently selected from    H or C₁-C₆ alkyl;-   alternatively, R²³ and R²⁴, together with the nitrogen to which they    are attached, form a 3-7 membered heterocyclic ring, wherein said    3-7 membered heterocyclic ring contains a nitrogen atom and    optionally a second atom selected from N, O and S; wherein said 3-7    membered heterocyclic ring is substituted with 0-1 C₁-C₄ alkyl;-   R^(23a) at each occurrence is each independently selected from H or    C₁-C₄ alkyl;-   R²⁵ at each occurrence is each independently selected from H or    C₁-C₆ alkyl; and-   R³⁰ is H, F, Cl, Br, —CF₃, C₁-C₆ alkyl, and C₁-C₆ alkoxy;    provided when ring A is

then X is —NR⁹R¹⁰.

In a preferred embodiment, W is CH.

In a preferred embodiment, ring A is

In a preferred embodiment, ring A is

In a preferred embodiment, ring A is

In a preferred embodiment, ring A is

In a preferred embodiment, R¹, R², R³, and R⁴ at each occurrence areindependently selected from H, halo, —OR¹¹, —NO₂, —CN, and —CF₃.

In a preferred embodiment, R¹ is H and R², R³, and R⁴ at each occurrenceare independently selected from H, halo, —OR¹¹, —NO₂, —CN, and —CF₃.

In a preferred embodiment, R¹, R³, and R⁴ are each H and R² is selectedfrom H, F, Cl, Br, —OCH₃, —NO₂, —CN, and —CF₃.

In a preferred embodiment, X is H, —NR⁹R¹⁰, halo, C₁-C₄ alkyl, or OR¹².

In a preferred embodiment, X is —NR⁹R¹⁰.

In a preferred embodiment, X is —NHR⁹.

In a preferred embodiment, R⁵ is H.

In another first embodiment, the present invention provides novelcompounds of Formula (II):

-   and stereoisomeric forms, mixtures of stereoisomeric forms,    tautomeric forms, prodrugs, or pharmaceutically acceptable salt    forms thereof, wherein:-   ring A is

-   R¹, R², R³, and R⁴ at each occurrence are independently selected    from    -   H, halo, —OR¹¹, —NO₂, —CN, —CF₃, —CHF₂, C₂-C₄ alkenyl, C₂-C₄        alkynyl, C₁-C₄ haloalkyl, and C₁-C₄ alkyl;-   R⁵ is H, C₁-C₆ alkyl or a prodrug of an amino group;-   R⁶ is selected from H;    -   C₁-C₆ alkyl substituted by 0-2 R²²;    -   C₂-C₆ alkenyl substituted by 0-2 R²²;    -   C₂-C₆ alkynyl substituted by 0-2 R²²; and    -   C₃-C₇ cycloalkyl substituted by 0-2 R²²;-   R⁷ is H, —NO₂, halo, C₁-C₄ alkyl or —NR²³R²⁴;-   X is H, —NR⁹R¹⁰, halo, OR¹², C₁-C₄ alkyl, or C₂-C₄ alkenyl;-   R⁹ and R¹⁰ at each occurrence are each independently selected from    H, —NH₂;    -   C₁-C₆ alkyl substituted by 0-1 R¹⁹;    -   C₂-C₆ alkenyl substituted by 0-1 R¹⁹;    -   C₂-C₆ alkynyl substituted by 0-1 R¹⁹;    -   C₆-C₁₀ aryl substituted by 0-5 R¹⁹;    -   C₃-C₇ carbocyclyl substituted by 0-5 R¹⁹; and    -   5 to 14 membered heterocyclyl group substituted by 0-5 R¹⁹,        wherein said heterocyclyl group comprises one, two, or three        heteroatoms selected from N, O, and S;    -   5 to 14 membered heteroaryl group substituted by 0-5 R¹⁹,        wherein said heteroaryl group comprises one, two, or three        heteroatoms selected from N, O, and S;-   alternatively, R⁹ and R¹⁰, together with the nitrogen to which they    are attached, form a 3-7 membered heterocyclic ring, wherein said    3-7 membered heterocyclic ring contains a nitrogen atom and    optionally a second atom selected from N, O, S, S(═O), and S(═O)₂,    wherein said 3-7 membered heterocyclic ring is substituted with 0-1    R¹⁷;-   R¹¹ at each occurrence is independently selected from H, C₁-C₄    alkyl, and C₁-C₄ haloalkyl;-   R¹² at each occurrence is independently selected from H, C₁-C₄    haloalkyl and C₁-C₄ alkyl substituted with 0-1 R¹⁹;-   R¹⁷ is H or C₁-C₄ alkyl substituted by 0-1 R¹⁹;-   R¹⁹ at each occurrence is independently selected from H, —NR²³R²⁴,    halo, —NO₂, —CN, —CF₃, C₁-C₄ haloalkyl, —NHOH, OR²⁵, C(═O)R²⁵,    C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴, NR^(23a)C(═O)R²⁵,    NR^(23a)CO₂R²⁵, C(═O)NR²³R²⁴, NR^(23a)C(═S)R²⁵, SR²⁵, S(═O)R²⁵,    S(═O)₂R²⁵; S(═O)₂NR²³R²⁴, —NR^(23a)S(═O)₂R²⁵,    -   C₁-C₄ alkyl substituted by 0-1 R³⁰;    -   C₂-C₄ alkenyl substituted by 0-1 R³⁰;    -   C₂-C₄ alkynyl substituted by 0-1 R³⁰;    -   C₆-C₁₀ aryl substituted by 0-5 R³⁰;    -   C₃-C₇ carbocyclyl substituted by 0-5 R³⁰; and    -   5 to 14 membered heterocyclyl group substituted by 0-5 R³⁰,        wherein said heterocyclyl group comprises one, two, or three        heteroatoms selected from N, O, and S;    -   5 to 14 membered heteroaryl group substituted by 0-5 R³⁰,        wherein said heteroaryl group comprises one, two, or three        heteroatoms selected from N, O, and S;-   R²² is H, —NR²³R²⁴, —N₃, halo, —NO₂, —CN, —CF₃, C₁-C₄ alkyl, C₂-C₄    alkenyl, C₂-C₄ alkynyl, C₁-C₄ haloalkyl, C₃-C₇ carbocyclyl, phenyl,    —NHOH, OR²⁵, —CH₂OR²⁵, C(═O)R²⁵, C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴,    NR^(23a)C(═O)R²⁵, NR^(23a)CO₂R²⁵, OC(═O)NR²³R²⁴, NR^(23a)C(═S)R²⁵,    SR²⁵, S(═O)R²⁵, S(═O)₂R²⁵; S(═O)₂NR²³R²⁴, or —NR^(23a)S(═O)₂R²⁵;-   R²³ and R²⁴ at each occurrence are each independently selected from    H or C₁-C₆ alkyl;-   alternatively, R²³ and R²⁴, together with the nitrogen to which they    are attached, form a 3-7 membered heterocyclic ring, wherein said    3-7 membered heterocyclic ring contains a nitrogen atom and    optionally a second atom selected from N, O and S, wherein said 3-7    membered heterocyclic ring is substituted with 0-1 C₁-C₄ alkyl;-   R^(23a) at each occurrence is each independently selected from H or    C₁-C₄ alkyl;-   R²⁵ at each occurrence is each independently selected from H or    C₁-C₆ alkyl; and-   R³⁰ is H, F, Cl, Br, —CF₃, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

In a preferred embodiment, ring A is

In a preferred embodiment, ring A is

In a preferred embodiment, ring A is

In a preferred embodiment, ring A is

In a preferred embodiment, R¹, R², R³, and R⁴ at each occurrence areindependently selected from H, F, Cl, Br, —OCH₃, —NO₂, —CN, and —CF₃.

In a preferred embodiment, R¹ is H and R², R³, and R⁴ at each occurrenceare independently selected from H, F, Cl, Br, —OCH₃, —NO₂, —CN, and—CF₃.

In a preferred embodiment, R¹, R³, and R⁴ are each H and R² is selectedfrom H, F, Cl, Br, —OCH₃, —NO₂, —CN, and —CF₃.

In a preferred embodiment, X is —NR⁹R¹⁰.

In a preferred embodiment, X is —NHR⁹.

In a preferred embodiment, R⁶ is C₁-C₆ alkyl substituted by 0-2 R²².

In a preferred embodiment, R⁶ is C₃-C₇ cycloalkyl substituted by 0-2R²².

In a preferred embodiment, R⁶ is cyclopentyl.

In another first embodiment, the present invention provides novelcompounds of Formula (III):

-   and stereoisomeric forms, mixtures of stereoisomeric forms,    tautomeric forms, prodrugs, or pharmaceutically acceptable salt    forms thereof, wherein:-   ring A is

-   R² is selected from    -   H, halo, —OR¹¹, —NO₂, —CN, —CF₃, —CHF₂, C₂-C₄ alkenyl, C₂-C₄        alkynyl, C₁-C₄ haloalkyl, and C₁-C₄ alkyl;-   R⁵ is H, methyl or a prodrug of an amino group;-   R⁶ is selected from H;    -   C₁-C₆ alkyl substituted by 0-2 R²²;    -   C₂-C₆ alkenyl substituted by 0-2 R²²;    -   C₂-C₆ alkynyl substituted by 0-2 R²²; and    -   C₃-C₇ cycloalkyl substituted by 0-2 R²²;-   X is H, —NR⁹R¹⁰, halo, OR¹², C₁-C₄ alkyl, or C₂-C₄ alkenyl;-   R⁹ and R¹⁰ at each occurrence are each independently selected from    H, —NH₂;    -   C₁-C₆ alkyl substituted by 0-1 R¹⁹;    -   C₂-C₆ alkenyl substituted by 0-1 R¹⁹;    -   C₂-C₆ alkynyl substituted by 0-1 R¹⁹;    -   C₆-C₁₀ aryl substituted by 0-5 R¹⁹;    -   C₃-C₇ carbocyclyl substituted by 0-5 R¹⁹; and    -   5 to 14 membered heterocyclyl group substituted by 0-5 R¹⁹,        wherein said heterocyclyl group comprises one, two, or three        heteroatoms selected from N, O, and S;    -   5 to 14 membered heteroaryl group substituted by 0-5 R¹⁹,        wherein said heteroaryl group comprises one, two, or three        heteroatoms selected from N, O, and S;-   alternatively, R⁹ and R¹⁰, together with the nitrogen to which they    are attached, form a 3-7 membered heterocyclic ring, wherein said    3-7 membered heterocyclic ring contains a nitrogen atom and    optionally a second atom selected from N, O, S, S(═O), and S(═O)₂,    wherein said 3-7 membered heterocyclic ring is substituted with 0-1    R¹⁷;-   R¹¹ at each occurrence is independently selected from H, C₁-C₄    alkyl, and C₁-C₄ haloalkyl;-   R¹² at each occurrence is independently selected from H, C₁-C₄    haloalkyl and C₁-C₄ alkyl substituted with 0-1 R¹⁹;-   R¹⁷ is H or C₁-C₄ alkyl substituted by 0-1 R¹⁹;-   R¹⁹ at each occurrence is independently selected from H, —NR²³R²⁴,    halo, —NO₂, —CN, —CF₃, C₁-C₄ haloalkyl, —NHOH, OR²⁵, C(═O)R²⁵,    C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴, NHC(═O)R²⁵, NHCO₂R²⁵,    OC(═O)NR²³R²⁴, NHC(═S)R²⁵, SR²⁵, S(═O)R²⁵, S(═O)₂R²⁵; S(═O)₂NR²³R²⁴,    —NHS(═O)₂R²⁵,    -   C₁-C₄ alkyl substituted by 0-1 R³⁰;    -   C₂-C₄ alkenyl substituted by 0-1 R³⁰;    -   C₂-C₄ alkynyl substituted by 0-1 R³⁰;    -   C₆-C₁₀ aryl substituted by 0-5 R³⁰;    -   C₃-C₇ carbocyclyl substituted by 0-5 R³⁰; and    -   5 to 14 membered heterocyclyl group substituted by 0-5 R³⁰,        wherein said heterocyclyl group comprises one, two, or three        heteroatoms selected from N, O, and S;    -   5 to 14 membered heteroaryl group substituted by 0-5 R³⁰,        wherein said heteroaryl group comprises one, two, or three        heteroatoms selected from N, O, and S;-   R²² is H, —NR²³R²⁴, —N₃, halo, —NO₂, —CN, —CF₃, C₁-C₄ alkyl, C₂-C₄    alkenyl, C₂-C₄ alkynyl, C₁-C₄ haloalkyl, C₃-C₇ carbocyclyl, phenyl,    —NHOH, OR²⁵, C(═O)R²⁵, C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴,    NHC(═O)R²⁵, NHCO₂R²⁵, OC(═O)NR²³R²⁴, NHC(═S)R²⁵, SR²⁵, S(═O)R²⁵,    S(═O)₂R²⁵; S(═O)₂NR²³R²⁴, or —NHS(═O)₂R²⁵;-   R²³ and R²⁴ at each occurrence are each independently selected from    H or C₁-C₄ alkyl;-   R²⁵ at each occurrence is each independently selected from H or    C₁-C₄ alkyl; and-   R³⁰ is H, F, Cl, Br, —CF₃, C₁-C₄ alkyl, and C₁-C₄ alkoxy.

In a preferred embodiment, R² is selected from H, F, Cl, Br, —OCH₃,—NO₂, —CN, and —CF₃.

In a preferred embodiment, R⁶ is cyclobutyl, cyclopentyl, or cyclohexyl.

In a preferred embodiment, R⁶ is cyclopentyl.

In a preferred embodiment, X is —NR⁹R¹⁰.

In a preferred embodiment, X is —NHR⁹.

In a preferred embodiment, R⁶ is cyclopentyl and X is —NR⁹R¹⁰.

In a preferred embodiment, R² is selected from F, Cl, Br, —OCH₃, —CN,and —CF₃; and X is —NR⁹R¹⁰.

In another first embodiment, the present invention provides novelcompounds of Formula (II):

-   and stereoisomeric forms, mixtures of stereoisomeric forms,    tautomeric forms or pharmaceutically acceptable salt forms thereof,    wherein:-   ring A is

-   R¹, R², R³, and R⁴ at each occurrence are independently selected    from H, F, Cl, Br, —OCH₃, —NO₂, —CN, and —CF₃;-   R⁵ is H;-   R⁶ is selected from H, methyl, ethyl, n-propyl, i-propyl, n-butyl,    i-butyl, n-pentyl, i-pentyl, allyl, cyclopentyl, cyclohexyl,    —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃, —CH₂CH₂CH₂N₃, and —CH₂CH₂CH₂NHCH₃;-   R⁷ is H or —NO₂;-   X is selected from H, Cl, methyl, ethyl, propyl, butyl,    -   —OH; —OCH₂CH₂N(CH₃)₂; —OCH₂CH₂(pyrid-3-yl);    -   —NHCH₃; —NCH₂CH₃; —NHCH(CH₃)₂; —NHCH₂CH₂CH₂CH₃; —NHCH₂CH(CH₃)₂;    -   —NHCH₂CH₂CF₃; —NHCH═CH₂; —NHCH₂CH═CH₂;    -   —NHCH₂CH₂N(CH₃)₂; —N(CH₃)CH₂CH₂N(CH₃)₂; —NHCH₂CH₂CH₂N(CH₃)₂;    -   —NHCH₂CH₂CH₂NH(CH₃);    -   —NHCH₂CH₂NH₂; —NHCH₂CH₂CH₂NH₂; —N(H)CH₂CH(NH₂)CH₃;    -   —N(CH₃)CH₂CH₂N(CH₂CH₃)₂; —NHNH₂; —NHCH₂CH₂NHC(═O)CH₃;    -   —N(CH₂CH₂OCH₃)₂; —N(H)CH₂CH₂OCH₃; —N(H)CH₂CH₂CH₂OCH₃;    -   —N(H)CH₂CH₂OCH₂CH₃; —N(H)CH₂CH₂OCH₂CH₂CH₃;    -   —N(CH₂CH₂OH)₂; —N(H)CH₂CH(OH)CH₃; —N(H)CH₂CH(OH)CH₂CH₃;    -   —N(H)CH₂CH(OH)CH₂OH;    -   —NH(pyrid-3-yl); —NH(4-F-pyrid-3-yl); —NH(4-MeO-pyrid-3-yl);        piperazin-1-yl;

In another first embodiment, the present invention provides novelcompounds of Formula (I) selected from the following Examples:

-   -   Example 30; Example 31; Example 32; Example 33; Example 34;        Example 35; Example 36; Example 37; Example 38; Example 39;        Example 40; Example 41; Example 42; Example 43; Example 45;        Example 46; Example 47; Example 48; Example 49; Example 50;        Example 51; Example 52; Example 53; Example 54; Example 55;        Example 56; Example 57; Example 58; Example 59; Example 60;        Example 61; Example 62; Example 63; Example 64; Example 65;        Example 66; Example 67; Example 68; Example 69; Example 70;        Example 71; Example 72; Example 73; Example 74; Example 75;        Example 76; Example 82; Example 83; Example 84; Example 85;        Example 86; Example 89; Example 90; Example 93; Example 94;        Example 95; Example 96; Example 97; Example 98; Example 99;        Example 100; Example 108; Example 109; Example 111; Example 113;        Example 114; Example 115; Example 116; Example 117; Example 118;        Example 119; Example 120; Example 121; Example 122; Example 123;        Example 124; Example 125; Example 126; Example 127; Example 128;        Example 129; Example 130; Example 131; Example 132; Example 133;        Example 134; Example 135; Example 136; Example 137; Example 138;        Example 139; Example 140; Example 141; Example 142; Example 143;        Example 144; Example 148; Example 149; Example 150; Example 151;        Example 152; Example 153; Example 154; Example 155; Example 156;        Example 157; Example 158; Example 159; Example 160; Example 161;        Example 162; Example 163; Example 164; Example 165; Example 166;        Example 167; Example 168; Example 169; Example 170; Example 171;        Example 172; Example 173; Example 174; Example 175; Example 176;        Example 177; Example 178; Example 179; Example 180; Example 181;        Example 182; Example 183; Example 184; Example 185; Example 186;        Example 187; Example 188; Example 189; Example 190; Example 191;        Example 192; Example 193; Example 194; Example 195; Example 196;        Example 197; Example 198; Example 199; Example 200; Example 201;        Example 202; Example 203; Example 204; Example 205; Example 211;        Example 212; Example 213; Example 214; Example 215; Example 216;        Example 217; Example 218; Example 219; Example 225; Example 226;        Example 227; Example 228; Example 229; Example 230; Example 231;        Example 232; Example 233; Example 234; Example 235; Example 236;        Example 237; Example 238; Example 239; Example 240; Example 241;        Example 242; Example 243; Example 244; Example 245; Example 246;        Example 247; Example 248; Example 249; Example 250; Example 251;        Example 252; Example 253; Example 254; Example 261; Example 262;        Example 263; Example 264; Example 265; Example 266; Example 267;        Example 268; Example 269; Example 270; Example 271; Example 272;        Example 273; Example 275; Example 276; Example 277; Example 278;        Example 279; Example 280; Example 287; Example 288; Example 289;        Example 290; Example 291; Example 292; Example 293; Example 294;        Example 295; Example 300; Example 301; Example 302; Example 303;        Example 304; Example 304; Example 305; Example 306; Example 307;        Example 309; Example 310; Example 314; Example 315; Example 316;        Example 317; Example 318; Example 319; Example 320; Example 321;        Example 322; Example 323; Example 324; Example 325; Example 326;        Example 327; Example 328; Example 329; Example 330; Example 331;        Example 332; Example 333; Example 334; Example 335; Example 336;        Example 337; Example 338; Example 339; Example 340; Example 341;        Example 342; Example 343; Example 344; Example 345; Example 346;        Example 347; Example 348; Example 349; Example 350; Example 351;        Example 352; Example 353; Example 354; Example 358; Example 359;        Example 360; Example 361; Example 362; Example 363; Example 364;        Example 365; Example 366; Example 367; Example 368; Example 369;        Example 370; Example 371; Example 372; Example 373; Example 374;        Example 375; Example 376; Example 377; Example 378; Example 379;        Example 380; Example 381; and Example 382;        and pharmaceutically acceptable salt forms thereof.

In a second embodiment, the present invention provides a method fortreatment of diseases comprising administering to a subject in needthereof a therapeutically effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, wherein the disease isselected from a chronic neurodegenerative disease, a neurotraumaticdisease, depression and diabetes.

In a preferred embodiment, the present invention provides a method oftreating or preventing chronic neurodegenerative diseases selected fromAlzheimer's Disease, Parkinson's Disease, progressive supranuclearpalsy, subacute panencephalitic parkinsonism, postencephaliticparkinsonism, dementia puglistica, guan-parkinsonial dementia complex,Pick's disease, corticobasal degeneration, frontotemporal dementia withparkinsonism, Huntington's disease, AIDS associated dementia,amyotrophic lateral sclerosis, and multiple sclerosis.

In a more preferred second embodiment the present invention provides amethod wherein the compound is administered for the treatment ofAlzheimer's Disease (AD).

In a third embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt or ester form thereof, and one or more pharmaceuticallyacceptable excipients.

In a preferred third embodiment, the present invention provides apharmaceutical composition comprising a therapeutically effective amountof compound of Formula (I), or a pharmaceutically acceptable salt orester form thereof, and one or more pharmaceutically acceptableexcipients.

In a fourth embodiment, the present invention provides for the use ofcompounds of formula (I) or pharmaceutically acceptable salts thereoffor the manufacture of a medicament for the treatment of a disease ordisorder, as disclosed herein.

These and other objects, features and advantages of the substitutedpyrazolopyrimidines will be disclosed in the following detaileddescription of the patent disclosure.

Definitions

The following terms and expressions contained herein are defined asfollows:

As used herein, the term “about” refers to a range of values from ±10%of a specified value. For example, the phrase “about 50 mg” includes±10% of 50, or from 45 to 55 mg.

As used herein, a range of values in the form “x-y” or “x to y”, or “xthrough y”, include integers x, y, and the integers there between. Forexample, the phrases “1-6”, or “1 to 6” or “1 through 6” are intended toinclude the integers 1, 2, 3, 4, 5, and 6. Preferred embodiments includeeach individual integer in the range, as well as any subcombination ofintegers. For example, preferred integers for “1-6” can include 1, 2, 3,4, 5, 6, 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, or 2-6, etc.

As used herein “stable compound” or “stable structure” refers to acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and preferably capable offormulation into an efficacious therapeutic agent. The present inventionis directed only to stable compounds.

As used herein, the term “alkyl” refers to a straight-chain, orbranched, alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isoamyl, neopentyl, 1-ethylpropyl, 3-methylpentyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, hexyl, etc. The alkyl moiety of alkyl-containinggroups, such as alkoxy, alkoxycarbonyl, and alkylaminocarbonyl groups,has the same meaning as alkyl defined above. Lower alkyl groups, whichare preferred, are alkyl groups as defined above which contain 1 to 4carbons, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, and tert-butyl. A designation such as “C₁-C₄ alkyl” refers toan alkyl radical containing from 1 to 4 carbon atoms.

As used herein, the term “alkenyl” refers to a straight-chain, orbranched, hydrocarbon group of 2 to 6 carbon atoms having at least onecarbon-carbon double bond. A designation “C₂-C₆ alkenyl” refers to analkenyl radical containing from 2 to 6 carbon atoms. Examples of alkenylgroups include, but are not limited to, ethenyl, propenyl, isopropenyl,butenyl, pentenyl, 2,4-pentadienyl, etc. Preferred alkenyl groupsinclude ethenyl and propenyl.

As used herein, the term “alkynyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 6 carbon atoms having at least onecarbon-carbon triple bond. A designation “C₂-C₆ alkynyl” refers to analkynyl radical containing from 2 to 6 carbon atoms. Examples include,but are not limited to, ethynyl, propynyl, isopropynyl, 3,5-hexadiynyl,etc.

As used herein, the term “alkylene” refers to a substituted orunsubstituted, branched or straight chained hydrocarbon of 1 to 6 carbonatoms, which is formed by the removal of two hydrogen atoms. Adesignation such as “C₁-C₄ alkylene” refers to an alkylene radicalcontaining from 1 to 4 carbon atoms. Examples include, but are notlimited to, methylene (—CH₂—), ethylene (—CH₂CH₂—), ethylidene(—CH(CH₃)—), propylene (—CH₂CH₂CH₂—), iso-propylene (—CH(CH₃)CH₂—),propylidene (—CH(CH₂CH₃)—), butylene (—CH₂CH₂CH₂CH₂—), etc.

As used herein, the term “cycloalkylene” refers to a saturated orpartially saturated mono- or bicyclic alkyl ring system containing 3 to10 carbon atoms, which is formed by the removal of two hydrogen atoms. Adesignation such as “C₃-C₆ cycloalkylene” refers to a cycloalkyl radicalcontaining from 3 to 6 ring carbon atoms. Preferred cycloalkylene groupsinclude those containing 3, 4, 5, or 6 ring carbon atoms. Examples ofcycloalkylene groups include such groups as cyclopropylene (—C₃H₄—),cyclobutylene (—C₄H₆—), cyclopentylene (—C₅H₈—), cyclopentenylene(—C₅H₆—), cyclohexylene (—C₆H₁₀—), and cyclohexenylene (—C₆H₈—).

As used herein, the term “phenylene” refers to a phenyl group with anadditional hydrogen atom removed, i.e. a moiety with the structure of(—C₆H₄—).

As used herein, the terms “carbocycle”, “carbocyclic” or “carbocyclyl”refer to a substituted or unsubstituted, stable monocyclic or bicyclichydrocarbon ring system which is saturated, partially saturated orunsaturated, and contains from 3 to 10 ring carbon atoms. Accordinglythe carbocyclic group may be aromatic or non-aromatic, and includes thecycloalkyl and aryl compounds defined herein. The bonds connecting theendocyclic carbon atoms of a carbocyclic group may be single, double,triple, or part of a fused aromatic moiety.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated mono- or bicyclic alkyl ring system containing 3 to 10 carbonatoms. A designation such as “C₃-C₇ cycloalkyl” refers to a cycloalkylradical containing from 3 to 7 ring carbon atoms. Preferred cycloalkylgroups include those containing 3, 4, 5, or 6 ring carbon atoms.Examples of cycloalkyl groups include such groups as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pinenyl,and adamantanyl.

As used herein, the term “cycloalkenyl” refers to partially unsaturatedmono- or bicyclic alkenyl ring system containing 5 to 10 carbon atoms. Adesignation such as “C₅-C₁₀ cycloalkenyl” refers to a cycloalkenylradical containing from 5 to 10 ring carbon atoms and one or more doublebonds. Preferred cycloalkenyl groups include those containing 5 or 7ring carbon atoms. Examples of cycloalkenyl groups include such groupsas cyclopentenyl, cyclohexenyl, and cycloheptenyl.

As used herein, the term “aryl” refers to a substituted orunsubstituted, mono- or bicyclic hydrocarbon aromatic ring system having6 to 10 ring carbon atoms. Examples include phenyl and naphthyl.Preferred aryl groups include unsubstituted or substituted phenyl andnaphthyl groups. Included within the definition of “aryl” are fused ringsystems, including, for example, ring systems in which an aromatic ringis fused to a cycloalkyl ring. Examples of such fused ring systemsinclude, for example, indane, indene, and tetrahydronaphthalene.

As used herein, the term “arylene” refers to an aryl group with anadditional hydrogen atom removed, i.e. an aryl group bonded through twocarbon atoms, for example phenylene.

As used herein, the term “heteroarylene” refers to a heteroaryl groupwith an additional hydrogen atom removed, i.e. a heteroaryl group bondedthrough two carbon atoms, for example furan-2,5-diyl; or a heteroarylgroup bonded through a carbon atom and a nitrogen atom, for examplepyrrol-1,2-diyl.

As used herein, the term “heterocycloalkylene” refers to aheterocycloalkyl group with an additional hydrogen atom removed, i.e. aheterocycloalkyl group bonded through two carbon atoms or aheterocycloalkyl group bonded through a carbon atom and a nitrogen atom.

As used herein, the terms “heterocycle”, “heterocyclic” or“heterocyclyl” refer to a substituted or unsubstituted carbocyclic groupin which the ring portion includes at least one heteroatom such as O, N,or S. The nitrogen and sulfur heteroatoms may be optionally oxidized,and the nitrogen may be optionally substituted in non-aromatic rings.Heterocycles are intended to include heteroaryl and heterocycloalkylgroups. Examples of heterocyclic groups include pyrrolyl, furanyl,thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, isoxazolyl,oxazolyl, oxathiolyl, oxadiazolyl, triazolyl, oxatriazolyl, furazanyl,tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,indolyl, isoindolyl, indazolyl, benzofuranyl, isobenzofuranyl, purinyl,quinazolinyl, quinolyl, isoquinolyl, benzoimidazolyl, benzothiazolyl,benzothiophenyl, thianaphthenyl, benzoxazolyl, benzisoxazolyl,cinnolinyl, phthalazinyl, naphthyridinyl, and quinoxalinyl, as well as,pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, pyrazalinyl, piperidyl, piperazinyl, morpholinyl,thiomorpholinyl, tetrahydrofuranyl, dithiolyl, oxathiolyl, dioxazolyl,oxathiazolyl, pyranyl, oxazinyl, oxathiazinyl, and oxadiazinyl.

As used herein, the term “heterocycloalkyl” refers to a 3 to 7 memberedcycloalkyl group in which one or more ring carbon atoms are replaced byat least one hetero atom such as —O—, —N—, or —S—. Examples ofheterocycloalkyl groups include pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, pyrazalinyl,piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl,dithiolyl, oxathiolyl, dioxazolyl, oxathiazolyl, pyranyl, oxazinyl,oxathiazinyl, and oxadiazinyl.

As used herein, the term “heteroaryl” refers to an aromatic groupcontaining 5 to 14 ring carbon atoms in which one or more ring carbonatoms are replaced by at least one hetero atom such as —O—, —N—, —S—, or—Se—. Examples of heteroaryl groups include pyrrolyl, furanyl, thienyl,pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl,oxathiolyl, oxadiazolyl, triazolyl, oxatriazolyl, furazanyl, tetrazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiadiazolyl,picolinyl, indolyl, isoindolyl, indazolyl, benzofuranyl,isobenzofuranyl, purinyl, quinazolinyl, quinolyl, isoquinolyl,benzoimidazolyl, benzothiazolyl, benzothiophenyl, thianaphthenyl,benzoxazolyl, benzisoxazolyl, cinnolinyl, phthalazinyl, naphthyridinyl,and quinoxalinyl. Included within the definition of “heteroaryl” arefused ring systems, including, for example, ring systems in which anaromatic ring is fused to a heterocycloalkyl ring. Examples of suchfused ring systems include, for example, phthalamide, phthalicanhydride, indoline, isoindoline, tetrahydroisoquinoline, chroman,isochroman, chromene, and isochromene.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, the term “haloalkyl” refers to an alkyl group having oneor more halogen substituents. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅, and the like. An alkyl group in whichall of the hydrogen atoms are replaced with halogen atoms can bereferred to as “perhaloalkyl.” Examples perhaloalkyl groups include CF₃and C₂F₅.

As used herein, the term “subject” or “mammal” refers to a warm bloodedanimal such as a mammal, preferably a human, or a human child, which isafflicted with, or has the potential to be afflicted with, one or morediseases and conditions described herein.

As used herein, a “therapeutically effective amount” refers to an amountof a compound of the present invention effective to prevent or treat thesymptoms of particular disorder. Such disorders include, but are notlimited to, those pathological and neurological disorders associatedwith the aberrant activity of the receptors described herein, whereinthe treatment or prevention comprises inhibiting, inducing, or enhancingthe activity thereof by contacting the receptor with a compound of thepresent invention.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem complicationscommensurate with a reasonable benefit/risk ratio.

As used herein, the term “unit dose” refers to a single dose which iscapable of being administered to a patient, and which can be readilyhandled and packaged, remaining as a physically and chemically stableunit dose comprising either the active compound itself, or as apharmaceutically acceptable composition, as described hereinafter.

All other terms used in the description of the present invention havetheir meanings as is well known in the art.

In another aspect, the present invention is directed to pharmaceuticallyacceptable salts of the compounds described above. As used herein,“pharmaceutically acceptable salts” includes salts of compounds of thepresent invention derived from the combination of such compounds withnon-toxic acid or base addition salts.

Acid addition salts include inorganic acids such as hydrochloric,hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acid, as wellas organic acids such as acetic, citric, propionic, tartaric, glutamic,salicylic, oxalic, methanesulfonic, para-toluenesulfonic, succinic, andbenzoic acid, and related inorganic and organic acids.

Base addition salts include those derived from inorganic bases such asammonium and alkali and alkaline earth metal hydroxides, carbonates,bicarbonates, and the like, as well as salts derived from basic organicamines such as aliphatic and aromatic amines, aliphatic diamines,hydroxy alkamines, and the like. Such bases useful in preparing thesalts of this invention thus include ammonium hydroxide, potassiumcarbonate, sodium bicarbonate, calcium hydroxide, methylamine,diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and thelike.

In addition to pharmaceutically-acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of the compounds, in the preparation of other salts, or inthe identification and characterization of the compounds orintermediates.

The pharmaceutically acceptable salts of compounds of the presentinvention can also exist as various solvates, such as with water,methanol, ethanol, dimethylformamide, ethyl acetate and the like.Mixtures of such solvates can also be prepared. The source of suchsolvate can be from the solvent of crystallization, inherent in thesolvent of preparation or crystallization, or adventitious to suchsolvent. Such solvates are within the scope of the present invention.

The present invention also encompasses the pharmaceutically acceptableprodrugs of the compounds disclosed herein. As used herein, “prodrug” isintended to include any compounds which are converted by metabolicprocesses within the body of a subject to an active agent that has aformula within the scope of the present invention. Since prodrugs areknown to enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.) the compounds of thepresent invention may be delivered in prodrug form. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Prodrugs, Sloane, K. B., Ed.;Marcel Dekker New York, 1992, incorporated by reference herein in itsentirety. Accordingly, prodrugs include, for example, compounds of thepresent invention wherein a hydroxy, amino, or carboxy group is bondedto any group that, when the prodrug is administered to a mammaliansubject, cleaves to form a free hydroxyl, free amino, or carboxylicacid, respectively. Examples include, but are not limited to, acetate,formate and benzoate derivatives of alcohol and amine functional groups;and alkyl, carbocyclic, aryl, and alkylaryl esters such as methyl,ethyl, propyl, iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, phenyl, benzyl, and phenethyl esters, and the like.

As used herein, “prodrug of an amino group” is intended to include achemical moiety bonded to an amino group on a compound of the presentinvention, wherein when the compound of the present invention isadministered to a mammalian subject, the chemical moiety bonded to theamino group cleaves to form a free amino, respectively. Examplesinclude, but are not limited to, acetate, formate and benzoatederivatives of amine functional groups, as well as alkyl-C(═O)—,alkenyl-C(═O)—, alkynyl-C(═O)—, carbocyclyl-C(═O)—,carbocyclylalkyl-C(═O)—, alkyl-S(═O)₂—, carbocyclyl-S(═O)₂—,carbocyclylalkyl-S(═O)₂—, alkyl-NHC(═O)—, carbocyclyl-NHC(═O)—,carbocyclylalkyl-NHC(═O)—, alkyl-OC(═O)—, carbocyclyl-OC(═O)—,carbocyclylalkyl-OC(═O)—, alkyl-NH—C(═O)—NHS(═O)₂—,carbocyclyl-NH—C(═O)—NHS(═O)₂—, alkyl-S(═O)₂—NH—C(═O)—, andcarbocyclyl-S(═O)₂—NH—C(═O)— groups.

It is recognized that compounds of the present invention may exist invarious stereoisomeric forms. As such, the compounds of the presentinvention include both diastereomers and enantiomers. The compounds arenormally prepared as racemates and can conveniently be used as such, butindividual enantiomers can be isolated or synthesized by conventionaltechniques if so desired. Such racemates and individual enantiomers andmixtures thereof form part of the present invention.

It is well known in the art how to prepare and isolate such opticallyactive forms. Specific stereoisomers can be prepared by stereospecificsynthesis using enantiomerically pure or enantiomerically enrichedstarting materials. The specific stereoisomers of either startingmaterials or products can be resolved and recovered by techniques knownin the art, such as resolution of racemic forms, normal, reverse-phase,and chiral chromatography, recrystallization, enzymatic resolution, orfractional recrystallization of addition salts formed by reagents usedfor that purpose. Useful methods of resolving and recovering specificstereoisomers described in Eliel, E. L.; Wilen, S. H. Stereochemistry ofOrganic Compounds; Wiley: New York, 1994, and Jacques, J, et al.Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, eachincorporated by reference herein in their entireties.

It is further recognized that functional groups present on the compoundsof Formula (I) may contain protecting groups. For example, the aminoacid side chain substituents of the compounds of Formula (I) can besubstituted with protecting groups such as benzyloxycarbonyl ort-butoxycarbonyl groups. Protecting groups are known per se as chemicalfunctional groups that can be selectively appended to and removed fromfunctionalities, such as hydroxyl groups and carboxyl groups. Thesegroups are present in a chemical compound to render such functionalityinert to chemical reaction conditions to which the compound is exposed.Any of a variety of protecting groups may be employed with the presentinvention. Preferred protecting groups include the benzyloxycarbonyl(Cbz; Z) group and the tert-butyloxycarbonyl (Boc) group. Otherpreferred protecting groups according to the invention may be found inGreene, T. W. and Wuts, P.G.M., “Protective Groups in Organic Synthesis”2d. Ed., Wiley & Sons, 1991.

Synthesis

The compounds of the present invention may be prepared in a number ofmethods well known to those skilled in the art, including, but notlimited to those described below, or through modifications of thesemethods by applying standard techniques known to those skilled in theart of organic synthesis. All processes disclosed in association withthe present invention are contemplated to be practiced on any scale,including milligram, gram, multigram, kilogram, multikilogram orcommercial industrial scale.

It will be appreciated that the compounds of the present invention maycontain one or more asymmetrically substituted carbon atoms, and may beisolated in optically active or racemic forms. Thus, all chiral,diastereomeric, racemic forms and all geometric isomeric forms of astructure are intended, unless the specific stereochemistry or isomericform is specifically indicated. It is well known in the art how toprepare such optically active forms. For example, mixtures ofstereoisomers may be separated by standard techniques including, but notlimited to, resolution of racemic forms, normal, reverse-phase, andchiral chromatography, preferential salt formation, recrystallization,and the like, or by chiral synthesis either from active startingmaterials or by deliberate chiral synthesis of target centers.

As will be readily understood, functional groups present on thecompounds of Formula (I) may contain protecting groups. For example, theamino acid side chain substituents of the compounds of Formula (I) canbe substituted with protecting groups such as benzyloxycarbonyl ort-butoxycarbonyl groups. Protecting groups are known per se as chemicalfunctional groups that can be selectively appended to and removed fromfunctionalities, such as hydroxyl groups and carboxyl groups. Thesegroups are present in a chemical compound to render such functionalityinert to chemical reaction conditions to which the compound is exposed.Any of a variety of protecting groups may be employed with the presentinvention. Preferred protecting groups include the benzyloxycarbonyl(Cbz; Z) group and the tert-butyloxycarbonyl (Boc) group. Otherpreferred protecting groups according to the invention may be found inGreene, T. W. and Wuts, P.G.M., “Protective Groups in Organic Synthesis”2d. Ed., Wiley & Sons, 1991.

General routes to prepare the Examples of the present invention areshown in the Schemes and examples that follow. The reagents and startingmaterials are commercially available and/or, using well-knowntechniques, can be readily synthesized by one of ordinary skill in theart. All substituents in the synthetic Schemes, unless otherwiseindicated, are as previously defined.

Compounds of invention can be synthesized following various syntheticschemes disclosed herein.

PATENT EXPERIMENTALS

The following Examples are exemplary only, and are not intended to limitthe invention.

Compound 2 and 3 3-Amino-1-cyclopentyl-1H-pyrazole-4-carbonitrile5-Amino-1-cyclopentyl-1H-pyrazole-4-carbonitrile

3-Amino-4-pyrazolecarbonitrile 1 (Acros, 4.32 g, 40.0 mmol),cyclopentylbromide (Acros, 7.15 g, 48 mmol) and anhydrous potassiumcarbonate (Fisher, 6.60 g, 48 mmol) were suspended in 30 mL anhydrousDMF and heated at 80° C. under argon overnight. An additional 3.5 g(23.5 mmol) of cyclopentylbromide and 3.3 g (24 mmol) of potassiumcarbonate were added and the reaction was subjected to an additional sixhours at 80° C. The reaction was permitted to cool and the DMF wasremoved on a rotary evaporator. Water was added (100 mL) and theorganics were extracted with dichloromethane (3×100 mL). The combineddichloromethane fractions were washed with water (50 mL) and brine (50mL) and were dried (magnesium sulfate). Concentration of the organicsafforded a solid which was subjected to flash chromatography on silicagel (2:1 hexane:ethyl acetate). Two white solids were obtained: 3 (1.67g, 24%) elutes first and 2 (4.56 g, 65%) elutes second. Compound 2: mp129-131° C.; MS (ES⁺ calculated: 176.22; found: 177.05 M+H). HPLC (100%purity, retention time 9.235 minutes—Method A); ¹H NMR (400 MHz,DMSO-d₆) δ 8.11 (s, 1H), 5.51 (br s, 2H), 4.45 (m, 1H), 1.97 (m, 2H),1.84 (m, 2H), 1.72 (m, 2H), 1.59 (m, 2H). Compound 3: mp 113° C.; MS(ES⁺ calculated: 176.22; found: 177.04 M+H). HPLC (88% purity, retentiontime 9.752 minutes—Method A); ¹H NMR (400 MHz, DMSO-d₆) δ 7.52 (s, 1H),5.75 (br s, 2H), 4.55 (m, 1H), 1.92 (m, 2H), 1.78 (m, 4H), 1.57 (m, 2H).

Pure compound 2 may be obtained without chromatography in 44% yield bytrituration of the crude solid with a minimum amount of dichloromethane.Compound 2 is relatively insoluble in dichloromethane whereas 3dissolves easily.

Compound 3 5-Amino-1-cyclopentyl-1H-pyrazole-4-carbonitrile

Alternate Synthesis of 3: Cyclopentylhydrazine hydrochloride¹ (1.08 g,10 mmol) was dissolved in 100 mL anhydrous ethanol. Sodium methoxide(540 mg, 10 mmol) was added in one portion and the reaction mixture wasstirred for ten minutes. Ethoxymethylenemalononitrile (Acros, 1.22 g, 10mmol) was then added in small portions over several minutes. Thereaction mixture was heated at 70° C. under argon overnight. Thereaction mixture was concentrated and subjected to flash chromatographyon silica gel (stepwise elution: dichloromethane followed by 1:1hexane:ethyl acetate) to afford 600 mg (34%) of compound 3—identical inall respects with the material obtained above.

Compound 5 and 6 1-Allyl-3-amino-1H-pyrazole-4-carbonitrile1-Allyl-5-amino-1H-pyrazole-4-carbonitrile

3-Amino-4-pyrazolecarbonitrile 1 (Acros, 1.08 g, 10.0 mmol),allylbromide (Acros, 1.45 g, 12 mmol) and anhydrous potassium carbonate(Fisher, 1.65 g, 12 mmol) were suspended in 10 mL anhydrous DMF andheated at 80° C. under argon overnight. The solution was concentrated.Water was added (100 mL) and the organics were extracted withdichloromethane (3×100 mL). The combined dichloromethane fractions werewashed with water (50 mL) and brine (50 mL) and were dried (magnesiumsulfate). Concentration of the organics afforded a solid which wassubjected to flash chromatography on silica gel (gradient elution 2:1 to3:2 hexane:ethyl acetate). 589 mg (40%) of a white solid was obtainedwhich was seen by NMR to contain an inseparable mixture of 5 and 6 in a2.1:1 ratio. This mixture was used without further purification.

Compound 7 and 8 3-Amino-1-cyclohexyl-1H-pyrazole-4-carbonitrile5-Amino-1-cyclohexyl-1H-pyrazole-4-carbonitrile

3-Amino-4-pyrazolecarbonitrile 1 (Acros, 6.48 g, 60.0 mmol),cyclohexylbromide (Acros, 11.74 g, 72 mmol), and anhydrous potassiumcarbonate (Fisher, 9.9 g, 72 mmol were combined in 40 mL of DMF andheated at 80° C. under argon overnight. The reaction was permitted tocool to room temperature. Water was added (100 mL) and the organics wereextracted with dichloromethane (3×100 mL). The combined dichloromethanefractions were washed with water (50 mL) and brine (50 mL) and weredried (magnesium sulfate). Concentration of the organics afforded asolid which was subjected to flash chromatography on silica gel(gradient elution 3:1 to 2:1 hexane:ethyl acetate). Separation of theisomers was not fully achieved but a few fractions containing pureproduct were combined to afford 7—a white solid (1.18 g, 10%). Compound7: mp 169-171° C.; HPLC (100% purity, retention time 8.416minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (s, 1H), 5.48 (br s,2H), 3.87 (m, 1H), 1.92 (m, 2H), 1.75 (m, 2H), 1.61 (m, 2H), 1.31 (m,2H), 1.16 (m, 2H).

Compound 8 5-Amino-1-cyclohexyl-1H-pyrazole-4-carbonitrile

Alternate Synthesis of Compound 8: Cyclohexanone (Acros, 19.6 g, 200mmol) and tert-butylcarbazate (Acros, 26.4 g, 200 mmol) were combined in350 mL dry hexane and stirred under argon for ½ hour. The mixture wasthen subjected to reflux temperature for 1.5 hours and permitted to coolto room temperature. A white solid formed on cooling which was removedby filtration and dried in vacuo—40.31 g (95%): mp 147-149° C.; MS (ES⁺calculated: 212.29; found: 235.05 M+Na). ¹H NMR (400 MHz, DMSO-d₆) δ9.47 (br s, 1H), 2.27 (m, 2H), 2.16 (m, 2H), 1.52 (m, 2H), 1.59 (m, 4H),1.42 (s, 9H).

t-Butylcarboxycyclohexanone hydrazone generated above (40.02 g, 189mmol) was dissolved in a mixture of 175 mL tetrahydrofuran and 225 mLanhydrous methanol. Sodium cyanoborohydride (Acros, 14.3 g, 227 mmol)was added in portions over ten minutes and the mixture was stirred underargon overnight at room temperature. 135 mL of 6N hydrochloric acid werethen added dropwise and the mixture was refluxed for one hour. Thereaction was permitted to cool to room temperature and a white solid wasremoved by filtration. The mother liquor was concentrated and residualwater was removed by azeotroping with ethanol on a rotary evaporator(3×100 mL). The mixture was concentrated to dryness and was taken upinto hot isopropanol (˜300 mL). The solid that was present was removedby filtration and the mother liquor was concentrated to ½ volume atwhich point an equal volume of ethyl ether was added. This causedcyclohexylhydrazine hydrochloride to precipitate as a white solid. Yield(20.0 g, 93%).

To cyclohexylhydrazine hydrochloride (7.52 g, 50 mmol) generated abovein 500 mL absolute ethanol was added sodium methoxide (Aldrich, 2.7 g,50 mmol). The mixture was stirred briefly and ethoxymethylmalononitrile(Acros, 6.11 g, 50 mmol) was added in small portions over twentyminutes. The reaction mixture was then heated at 70° C. under argonovernight. On cooling, the reaction was concentrated and subjected toflash chromatography on silica gel (1:1 hexane:ethyl acetate) affording6.3 g (66%) of a light brown solid. Compound 8: mp 99-103° C.; MS (ES⁺calculated: 190.25; found: 191.15 M+H). HPLC (97% purity, retention time11.135 minutes—Method A); ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (s, 1H), 6.49(br s, 2H), 4.02 (m, 1H), 1.80-1.10 (m, 10H).

Compound 10 and 11 3-Amino-1-cyclohexyl-1H-pyrazole-4-carboxylic acidethyl ester 5-Amino-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethylester

Ethyl-3-Aminopyrazole-4-carboxylate 9 (Acros, 15.5 g, 100.0 mmol),cyclohexylbromide (Acros, 21.9 g, 130 mmol), anhydrous potassiumcarbonate (Fisher, 27.6 g, 200 mmol), Adogen 464 (Acros, 2.5 g) andaqueous sodium hydroxide (0.1 mL of a 12.5M solution) were combined in250 mL of toluene and refluxed under argon overnight. Additionalcyclohexylbromide (21.9 g, 130 mmol) and potassium carbonate (27.6 g,200 mmol) were then added and the reaction mixture was resubjected tothe reaction conditions for an additional 24 hours. The reaction waspermitted to cool to room temperature and the organics were washed with100 mL water. The organic layer was separated and dried (magnesiumsulfate). Concentration of the organics afforded a solid which wassubjected to flash chromatography on silica gel (gradient elution 9:1 to6:1 to 3:1 hexane:ethyl acetate) to afford two principle products.Compound 11 (923 mg, 4%) elutes first and Compound 10 (1.755 g, 7%)elutes second. A considerable amount of material was present in mixedfractions. Compound 10: MS (ES⁺ calculated: 237.30; found: 238.10 M+H).HPLC (98% purity, retention time 13.623 minutes—Method A); ¹H NMR (400MHz, DMSO-d₆) δ 7.44 (s, 1H), 6.19 (br s, 2H), 4.43 (q, J=7 Hz, 2H),4.05 (m, 1H), 1.83-1.22 (m, 10H), 1.23 (t, J=7 Hz, 3H). Compound 11: MS(ES⁺ calculated: 237.30; found: 238.14 M+H). HPLC (100% purity,retention time 13.408 minutes—Method A); ¹H NMR (400 MHz, DMSO-d₆) δ7.87 (s, 1H), 5.29 (br s, 2H), 4.15 (q, J=7 Hz, 2H), 3.89 (m, 1H),1.97-1.25 (m, 10H), 1.24 (t, J=7 Hz, 3H).

Compound 12 3-Amino-1-cyclopentyl-1H-pyrazole-4-carboxylic acid amide

To concentrated sulfuric acid (Fisher, 8 mL) at 0° C. was added 2 (4.24g, 24.0 mmol) in small portions. The reaction was permitted to warm toroom temperature and was stirred for two hours. At the end of thisperiod all solid had dissolved. This viscous mixture was then addedslowly (violent) to 100 mL concentrated ammonium hydroxide solution(Fisher). The mixture was stirred for ten minutes and the white solidthat formed was collected by filtration, was washed with water, and wasdried in vacuo. Yield: 3.838 g (82%). Compound 12: mp 179-181° C.; MS(ES⁺ calculated: 194.24; found: 195.12 M+H). HPLC (100% purity,retention time 5.225 minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ 7.94(s, 1H), 7.14 (br s, 1H), 6.67 (br s, 1H), 5.32 (br s, 2H), 4.39 (m,1H), 1.97 (m, 2H), 1.83 (m, 2H), 1.72 (m, 2H), 1.61 (m, 2H).

Compound 13 1-Allyl-3-amino-1H-pyrazole-4-carboxylic acid amide1-Allyl-5-amino-1H-pyrazole-4-carboxylic acid amide

The mixture of solids derived from the preparation of 5 and 6 (589 mg,4.0 mmol) was treated with concentrated sulfuric acid (1 mL) as for thepreparation of 12 above. Following neutralization with concentratedammonium hydroxide (10 mL) and filtration a mass of white solid wasobtained which shrank considerably when washed with water. The resultingproduct was dried in vacuo affording 282 mg (42%) of 13 as a whitesolid. Compound 14 was determined to be present in the water wash butwas not isolated from this reaction. Compound 13: mp 100-101° C.; MS(ES⁺ calculated: 166.18; found: 167.12 M+H). HPLC (94% purity, retentiontime 5.141 minutes—Method A); ¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (s, 1H),7.19 (br s, 1H), 6.69 (br s, 1H), 5.95 (m, 1H), 5.34 (br s, 2H), 5.22(d, J=1 Hz, 1H), 5.22 (m, 1H), 5.17 (m, 1H), 4.48 (d, J=6 Hz, 2H).

Compound 15 5-Amino-1-cyclohexyl-1H-pyrazole-4-carboxylic acid amide

Compound 8 (6.3 g, 33.2 mmol) was treated with concentrated sulfuricacid (12 mL) as for the preparation of 12 above. The product wasisolated via neutralization with concentrated ammonium hydroxide (225mL), washing with water, and drying in vacuo as described for 12. 4.04 g(58%) of a white solid, Compound 15 were obtained. Compound 15: mp274-278° C.; MS (ES⁺ calculated: 208.27; found: 209.14 M+H). HPLC (97%purity, retention time 6.498 minutes—Method A); ¹H NMR (400 MHz,DMSO-d₆) δ 7.61 (s, 1H), 7.08 (br s, 1H), 6.58 (br s, 1H), 6.14 (br s,2H), 3.97 (m, 1H), 1.86-1.58 (m, 7H), 1.44-1.28 (m, 2H), 1.28-1.06 (m,1H).

Compound 16 5-Amino-1-cyclopentyl-1H-pyrazole-4-carboxylic acid amide

Compound 3 (3.34 g, 19.0 mmol) was treated with concentrated sulfuricacid (6 mL) as for the preparation of 12 above. The product was isolatedvia neutralization with concentrated ammonium hydroxide (80 mL), washingwith water, and drying in vacuo as described for 12. 3.64 g (99%) of afluffy white powder, Compound 16, was obtained. Compound 16: MS (ES⁺calculated: 194.24; found: 195.10 M+H). HPLC (97%) purity, retentiontime 1.739 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ 7.62 (s, 1H),7.10 (br s, 1H), 6.60 (br s, 1H), 6.14 (br s, 2H), 4.52 (m, 1H),1.97-1.67 (m, 6H), 1.63-1.50 (m, 2H).

Compound 17 2-Cyclopentyl-2,5-dihydro-pyrazolo[3 ,4-d]pyrimidin-4-one

Compound 12 (3.87 g, 20 mmol) was suspended in 60 mLtriethylorthoformate (Acros) and refluxed under argon overnight (˜150°C.). The reaction was concentrated and the solid obtained was trituratedin ether, collected by filtration, and dried in vacuo to afford 3.782 g(93%) of a white solid. Compound 17: mp 271-273° C.; MS (ES⁺ calculated:204.23; found: 205.06 M+H). HPLC (100%) purity, retention time 6.104minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ 11.65 (br s, 1H), 8.55(s, 1H), 7.91 (s, 1H), 4.86 (m, 1H), 2.12 (m, 2H), 2.00 (m, 2H), 1.83(m, 2H), 1.66 (m, 2H). Compound 17 may also be prepared from 12 byrefluxing with 2 equivalents of formamidine acetate in methoxyethanol.Concentration of the solution at the end of the reaction andneutralizing with ammonium hydroxide solution generates 17 identical inall respects with that derived from the triethylorthoformate procedure.

Compound 18 2-Cyclohexyl-2,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Compound 10 (1.8 g, 7.6 mmol) was combined with formamidine acetate(Acros, 1.58 g, 15.2 mmol) in 50 mL methoxyethanol (Acros) and refluxedunder argon overnight. Starting material was still evident. Additionalformamidine acetate (700 mg, 6.7 mmol) was added and the mixture wasrefluxed an additional 24 hours. The reaction was concentrated and thesolid was treated with 100 mL 0.1N ammonium hydroxide solution. Theproduct was then isolated by filtration, was washed with water, and wasdried in vacuo to afford 1.03 g (62%) of a tan solid. Compound 18: mp287-289° C.; MS (ES⁻ calculated: 218.26; found: 217.54 M−H). HPLC (97%)purity, retention time 7.959 minutes—Method A); ¹H NMR (400 MHz,DMSO-d₆) δ 11.64 (br s, 1H), 8.53 (s, 1H), 7.90 (s, 1H), 4.30 (m, 1H),2.03 (m, 2H), 1.86-1.58 (m, 5H), 1.39 (m, 2H), 1.22 (m, 1H).

Compound 19 2-Allyl-2,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

Compound 13 (282 mg, 1.70 mmol) was refluxed under argon in 5 mLtriethylorthoformate overnight. The reaction was concentrated and thecrude product was triturated with cold ethanol. Filtration afforded awhite solid which was dried in vacuo to afford 111 mg (37%). Compound19: mp 222-224° C.; MS (ES⁺ calculated: 176.18; found: 177.03 M+H). HPLC(100%) purity, retention time 7.395 minutes—Method A); ¹H NMR (400 MHz,DMSO-d₆) δ 11.70 (br s, 1H), 8.50 (s, 1H), 7.91 (s, 1H), 6.08 (m, 1H),5.26 (d, J=10 Hz, 1H), 5.20 (d, J=15 Hz, 1H), 4.91 (d, J=6 Hz, 2H).

Compound 20 1-Cyclopentyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

In a similar fashion as for the preparation of 19, compound 16 (3.639 g,18.8 mmol) was refluxed in 75 mL triethylorthoformate affording 3.111 g(81%) of 20 as white crystals. Compound 20: mp 235-237° C.; MS (ES⁺calculated: 204.23; found: 205.19 M+H). HPLC (100%) purity, retentiontime 2.674 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (br s,1H), 8.05 (s, 1H), 5.13 (m, 1H), 2.07 (m, 2H), 1.96 (m, 2H), 1.86 (m,2H), 1.67 (m, 2H).

Compound 21 1-Cyclohexyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

In a similar fashion as for the preparation of 18, compound 15 (4.04 g,19.4 mmol) was reacted with formamidine acetate (4.03 g, 38.8 mmol) in100 mL methoxyethanol to afford 3.717 g (88%) of 21 as a tan solid.Compound 21: mp 255-257° C.; MS (ES⁻ calculated: 218.26; found: 217.15M−H). HPLC (98%) purity, retention time 7.564 minutes—Method B); ¹H NMR(400 MHz, DMSO-d₆) δ 12.13 (br s, 1H), 8.14 (s, 1H), 4.56 (m, 1H),1.98-1.58 (m, 6H), 1.69 (m, 1H), 1.42 (m, 2H), 1.22 (m, 1H).

Compound 22 4-Chloro-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidine

N,N-Dimethylaniline (Acros, 10 mL) was added to Compound 17 (3.10 g,13.9 mmol) dissolved in phosphorus oxychloride (Acros, 90 mL) and themixture was refluxed under argon at 110° C. for 90 minutes. Excessphosphorus oxychloride was removed in vacuo and the dark syrup waspoured into ice water. The organics were extracted with three 50 mLportions of ether. The ether extracts were combined, were washed withwater and brine, and were dried (magnesium sulfate). Concentration ofthe ether afforded a dark oil which was purified by flash chromatographyon silica gel (gradient elution: 1-3% methanol: dichloromethane) toafford 2.74 g (88%) of a green oil. Compound 22: MS (ES⁺ calculated:222.68; found: 223.12 M+H). HPLC (85%) purity, retention time 9.882minutes—Method B); ¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 1H), 8.17 (s, 1H),4.99 (m, 1H), 2.28 (m, 2H), 2.19 (m, 2H), 2.00 (m, 2H), 1.78 (m, 2H).

Compound 23 4-Chloro-2-cyclohexyl-2H-pyrazolo[3,4-d]pyrimidine

In a similar fashion as for the preparation of Compound 22, Compound 23(0.50 g, 2.29 mmol) was treated with 25 mL phosphorus oxychloride and 3mL N,N-dimethylaniline. Following flash chromatography on silica gel(gradient elution: 1-3% methanol: dichloromethane) there was obtained360 mg (66%) of a yellow-green oil. Compound 23: MS (ES⁺ calculated:236.71; found: 237.24 M+H). HPLC (94%) purity, retention time 10.416minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.79 (s,1H), 4.59 (m, 1H), 2.12 (m, 2H), 1.93-1.86 (m, 4H), 1.70 (m, 1H), 1.46(m, 2H), 1.27 (m, 1H).

Compound 24 4-Chloro-2-cyclohexyl-2H-pyrazolo[3,4-d]pyrimidine

In a similar fashion as for the preparation of Compound 22, Compound 19(110 mg, 0.63 mmol) was treated with 5 mL phosphorus oxychloride and 0.5mL N,N-dimethylaniline. Following flash chromatography on silica gel(gradient elution: 1-3-5% methanol: dichloromethane) 77 mg (63%) of adark yellow oil was obtained. Compound 24: MS (ES⁺ calculated: 194.62;found: 195.07 M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (s, 1H), 7.92 (s,1H), 6.04 (m, 1H), 5.33-5.11 (m, 2H), 4.92 (m, 2H).

Compound 25 4-Chloro-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine

In a similar fashion as for the preparation of compound 22, Compound 20(1.5 g, 7.35 mmol) was treated with 75 mL phosphorus oxychloride and 6mL N,N-dimethylaniline. The reaction was subjected to an ether work-upas for 22 above (without columning) to afford 1.734 g (quantitative) ofa yellow solid which was used without further purification. Compound 25:MS (ES⁺ calculated: 222.68; found: 223.19 M+H).

Compound 26 4-Chloro-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidine

In a similar fashion as for the preparation of Compound 22, Compound 21(1.5 g, 6.88 mmol) was treated with 70 mL phosphorus oxychloride and 6mL N,N-dimethylaniline. The reaction was subjected to an ether work-upas for 22 above (without columning) to afford 800 mg (of a dark yellowoil which was used without further purification. Compound 26: MS (ES⁺calculated: 236.71; found: 237.18 M+H).

Example 293-[9-((1R,2S,3R,4R)-2,3-Dihydroxy-4-methoxymethyl-cyclopentyl)-9H-purin-6-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

To 5-cyanooxindole (Combiblocks, 50.6 mg, 0.32 mmol) andN,N,N′,N′-tetramethylethylenediamine (Acros, 0.10 mL, 0.64 mmol) in 10mL anhydrous THF under argon at −78° C. was added lithiumdiisopropylamine (Acros, 0.32 mL of a 2.0M solution in THF/heptane, 0.64mmol). The solution was stirred for fifteen minutes at which point asolution of Compound 27 (104 mg, 0.307 mmol) in 10 mL THF was addeddropwise at such a rate as to maintain the temperature below −50° C. Thereaction was stirred for ten minutes, external cooling was removed, andthe reaction was permitted to warm to room temperature. An oil bath wasapplied and the mixture was refluxed overnight. The reaction wasconcentrated, water (50 mL) was added and the organics were extractedinto dichloromethane (3×50 mL). The dichloromethane extracts werecombined, were washed with water (50 mL) and brine (50 mL) and weredried (magnesium sulfate). Removal of the dichloromethane followed byflash chromatography on silica gel (gradient elution: 1-3% methanol:dichloromethane) afforded ˜60 mg of an acetonide [MS (ES⁺ calculated:460.50; found: 461.24 M+H)] which was treated immediately with a mixtureof trifluoroacetic acid (24 mL) and water (3 mL) for 30 minutes at roomtemperature. The reaction mixture was concentrated and partitionedbetween saturated sodium bicarbonate solution (50 mL) anddichloromethane (50 mL). A solid formed at the interface which wasfiltered off. [The dichloromethane layer was determined to contain onlypolar impurities.] The material isolated at the interface was washedwith water and was dried in vacuo to afford 15 mg (12%) of the diol as ayellow solid. Example 29: mp 230-236° C. (dec); MS (ES⁺ calculated:420.43; found: 421.21 M+H). HPLC (95%) purity, retention time 8.089minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (br s, 1H), 9.60(s, 1H), 8.68 (s, 1H), 8.61 (s, 1H), 7.38 (d, J=7 Hz, 1H), 7.04 (d, J=7Hz, 1H), 5.06 (m, 1H), 4.82 (m, 2H), 4.33 (m, 1H), 3.83 (m, 1H), 3.46(m, 1H), 3.28 (s, 3H), 2.31 (m, 1H), 2.17 (m, 1H), 1.67 (m, 1H).

Example 303-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

To 5-cyanooxindole (Combiblocks, 158.2 mg, 1.00 mmol) in 10 mL anhydroustetrahydrofuran under argon was addedN,N,N′,N′-tetramethylethylenediamine (Acros, 0.30 mL, 2.00 mmol). Thesolution was cooled to −78° C. and lithium diisopropylamide (Acros, 1.0mL of a 2.0M solution in THF/hexane, 2.00 mmol) was added dropwise. Thereaction was stirred for fifteen minutes at which point a solution ofCompound 22 (236 mg, 1.06 mmol) in 10 mL anhydrous tetrahydrofuran wasadded dropwise. The reaction was stirred an additional fifteen minutesand was warmed to room temperature for ½ hour. The mixture was thenrefluxed overnight. The reaction was quenched by addition of a smallamount of a saturated ammonium chloride solution and concentrated.Dichloromethane (50 mL) and water (50 mL) were added and undissolvedsolid was filtered off. The solid was washed with dichloromethane andwas taken up into a small amount of N,N-dimethylformamide andconcentrated onto a small amount of silica gel. The silica containingproduct was applied to the top of a silica gel column and flashchromatography was effected (gradient elution: 1-3-5-10% methanol:dichloromethane to 1% ammonium hydroxide:10% methanol:89%dichloromethane) to afford 124 mg (36%) of a yellow-orange solid.Example 30: mp>300° C. (dec); MS (ES⁺ calculated: 344.28; found: 345.17M+H). HPLC (100%) purity, retention time 12.154 minutes—Method B); ¹HNMR (400 MHz, DMSO-d₆) δ 13.17 (br s), 11.25 (s), 10.81 (br s), 10.61(br s), 9.57 (s), 9.10 (s), 8.76 (s), 8.40 (s), 8.23 (br s), 8.14 (brs), 7.99 (s), 7.50 (d, J=9 Hz), 7.42 (m),7.07 (d, J=8 Hz), 6.92 (m),5.22 (m), 4.97 (m), 3.25 (m), 2.25-1.53 (m, 8H).

Example 315-Bromo-3-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 30 above, 5-bromooxindole(Combiblocks, 99.6 mg, 0.47 mmol) was reacted with Compound 22 (110 mg,0.5 mmol). Upon completion, the reaction was concentrated and the crudeproduct obtained was purified by flash chromatography on silica gel(gradient elution: 1-3-5-10% methanol: dichloromethane) to afford 143 mg(76%) of a yellow solid. Example 31: mp 319-322° C. (dec); MS (ES⁺calculated: 398.27; found: 398.44, 399.81 M+H). HPLC (100%) purity,retention time 13.050 minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ10.88 (s), 10.27 (br s), 9.57 (s), 8.86 (s), 8.34 (d, J=3 Hz), 8.25 (brs), 7.74 (s), 7.21 (dd, J=2.9 Hz), 7.12 (d, J=7 Hz), 6.89 (d, J=8 Hz),6.74 (d, J=8 Hz), 5.14 (m), 4.94 (m), 3.17 (d, J=5 Hz), 2.28-1.56 (m,8H).

Example 32 6-Chloro-3-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 31 above,6-chlorooxindole (Combiblocks, 78.7 mg, 0.47 mmol) was reacted withCompound 22 (110 mg, 0.5 mmol). The crude product was purified by flashchromatography on silica gel (gradient elution: 1-3-5% methanol:dichloromethane) to afford 67 mg (40%) of a rust colored solid. Example32: mp 294-296° C.; MS (ES⁺ calculated: 353.81; found: 354.27 M+H). HPLC(86%) purity, retention time 12.997 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 10.89 (s), 10.29 (br s), 9.55 (s), 8.97 (s), 8.33 (d, J=3Hz), 8.17 (br s), 7.74 (d, J=8 Hz), 7.69 (m), 7.02 (dd, J=2.8 Hz), 6.94(d, J=2 Hz), 6.81 (s), 5.13 (m), 4.93 (m), 4.19 (m), 3.33 (m), 2.22-1.53(m, 8H).

Example 333-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitro-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 31 above, 5-nitrooxindole(Combiblocks, 50 mg, 0.28 mmol) was reacted with Compound 22 (63 mg,0.284 mmol). The crude product was purified by flash chromatography onsilica gel (gradient elution: 1-3-5% methanol: dichloromethane) toafford 30 mg (29%) of a rust colored solid. Example 33: MS (ES⁻calculated: 364.37; found: 364.03 M+). HPLC (76%) purity, retention time11.582 minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ 13.73 (br s),12.75 (br s), 11.40 (s), 10.84 (s), 10.73 (s), 9.63 (s), 9.58 (s), 9.27(s), 9.19 (br s), 8.98 (s), 8.50 (m), 8.41 (s), 7.92 (m), 7.69 (m), 7.10(m), 6.92 (m), 4.96 (m), 4.24 (m), 4.06 (m), 3.17 (m), 2.22-1.70 (m, 8H).

Example 34 3-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-trifluoromethyl-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 31 above,5-trifluoromethyloxindole (Combiblocks, 55.3 mg, 0.275 mmol) was reactedwith Compound 22 (63 mg, 0.284 mmol). The crude product was purified byflash chromatography on silica gel (gradient elution: 1-3-5% methanol:dichloromethane) to afford 90 mg (84%) of a golden solid. Example 34: mp292-293° C.; MS (ES⁺ calculated: 387.37; found: 388.18 M+H). HPLC (96%)purity, retention time 13.212 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 13.92 (s), 12.50 (br s), 11.12 (s), 10.53 (s), 9.63 (s), 9.59(s), 8.79 (s), 8.74 (s), 8.57 (br s), 8.40 (s), 8.37 (s), 8.31 (s), 7.87(s), 7.39 (d, J=8 Hz), 7.31 (d, J=7 Hz), 7.10 (d, J=8 Hz), 6.94 (d, J=7Hz), 5.05 (m), 4.95 (m), 3.18 (s), 2.27-1.55 (m, 8H).

Example 353-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5,7-difluoro-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 31 above,5,7-difluoromethyloxindole (Combiblocks, 47 mg, 0.28 mmol) was reactedwith Compound 22 (65 mg, 0.293 mmol). The crude product was purified byflash chromatography on silica gel (gradient elution: 1-3-5% methanol:dichloromethane) to afford 19 mg (19%) of a yellow solid. Example 35: mp296-297° C.; MS (ES⁺ calculated: 355.35; found: 386.16 M+H). HPLC (98%)purity, retention time 12.219 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 11.19 (br s), 11.23 (s), 10.57 (s), 9.60 (s), 9.02 (s), 8.40(s), 8.27 (s), 7.94 (m), 7.72 (m), 7.39 (d, J=9 Hz), 6.96 (m), 6.84 (m),5.21 (m), 4.96 (m), 2.33-1.56 (m, 8H).

Example 36 5-Chloro-3-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 31 above,5-chlorooxindole (Combiblocks, 47 mg, 0.28 mmol) was reacted withCompound 22 (65 mg, 0.293 mmol). The crude product was purified by flashchromatography on silica gel (gradient elution: 1-3-5% methanol:dichloromethane) to afford 73 mg (74%) of a yellow solid. Example 36: mp290-292° C.; MS (ES⁺ calculated: 353.81; found: 354.26 M+H). HPLC (80%)purity, retention time 12.595 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 10.87 (s), 10.24 (br s), 9.57 (s), 8.91 (s), 8.35 (d, J=5Hz), 8.23 (br s), 7.63 (s), 7.09 (dd, J=2.8 Hz), 6.98 (d, J=8 Hz), 6.93(d, J=8 Hz), 6.77 (d, J=8 Hz), 5.17 (m), 4.94 (m), 4.07 (m), 3.17 (d,J=5 Hz), 2.28-1.61 (m, 8H).

Example 373-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indo-2-one

In a similar fashion as for the preparation of 31 above, 5-hydroxyindole(Combiblocks, 45 mg, 0.338 mmol) was reacted with Compound 22 (75 mg,0.338 mmol). The crude product was purified by flash chromatography onsilica gel (gradient elution: 1-3-5% methanol: dichloromethane) toafford 70 mg (65%) of a yellow-orange solid. Example 37: mp 289-292° C.;MS (ES⁺ calculated: 319.37; found: 320.18 M+H). HPLC (87%) purity,retention time 11.043 minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ10.76 (s), 10.22 (br s), 9.55 (br s), 8.98 (s), 8.30 (s), 8.17-7.86 (m),7.78 (s), 7.06 (s), 6.94 (s), 5.14 (m), 4.97 (m), 2.59 (d, J=5 Hz),2.27-1.55 (m, 8H).

Example 38 3-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile

In a similar fashion as for the preparation of 31 above, 6-cyanooxindole(Combiblocks, 80 mg, 0.506 mmol) was reacted with Compound 22 (111 mg,0.5 mmol). The crude product was purified by flash chromatography onsilica gel (gradient elution: 1-3-5-10% methanol: dichloromethane) toafford 49 mg (28%) of a yellow solid. Example 38: mp 340-344° C.; MS(ES⁺ calculated: 344.38; found: 345.17 M+H). HPLC (98%) purity,retention time 11.243 minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ11.66 (s), 11.06 (br s), 9.58 (s), 9.05 (s), 8.40 (d, J=2 Hz), 8.26 (brs), 8.03 (d, J=8 Hz), 7.42 (d, J=8 HzO, 7.31 (d, J=8 Hz), 7.15 (t, J=8Hz), 7.03 (t, J=8 Hz), 5.16 (m), 4.97 (m), 4.08 (m), 2.27-1.55 (m, 8H).

Example 393-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-7-carbonitrile

In a similar fashion as for the preparation of 31 above, 7-cyanooxindole(Combiblocks, 80 mg, 0.506 mmol) was reacted with Compound 22 (111 mg,0.5 mmol). The crude product was purified by flash chromatography onsilica gel (gradient elution: 1-3-5% methanol: dichloromethane) toafford 31 mg (18%) of a yellow solid. Example 39: mp>380° C.; MS (ES⁺calculated: 344.38; found: 345.16 M+H). HPLC (100%) purity, retentiontime 11.424 minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ 14.29 (s),11.09 (s), 10.48 (br s), 9.61 (s), 9.07 (s), 8.43 (s), 8.40 (m), 7.90(d, J=8 Hz), 7.40 (dd, J=2.8 Hz), 7.35 (m), 7.25 (d, J=2 Hz), 7.08 (brs), 5.17 (m), 4.98 (m), 4.08 (m), 2.27-1.60 (m, 8H).

Example 403-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-fluoro-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 31 above,5-fluorooxindole (Combiblocks, 76 mg, 0.50 mmol) was reacted withCompound 22 (111 mg, 0.5 mmol). The crude product was purified by flashchromatography on silica gel (gradient elution: 1-3-5% methanol:dichloromethane) to afford 82 mg (49%) of a yellow solid. Example 40: mp256-260° C.; MS (ES⁺ calculated: 337.36; found: 338.18 M+H). HPLC (99%)purity, retention time 11.783 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 10.77 (s), 10.10 (s), 9.59 (s), 9.00 (s), 8.34 (s), 8.21 (s),8.02 (m), 7.51 (d, J=10 Hz), 6.90 (m), 6.75 (m), 5.20 (m), 4.93 (m),2.22-1.56 (m, 8H).

Example 413-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-6-fluoro-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 31 above,6-fluorooxindole (Combiblocks, 76 mg, 0.50 mmol) was reacted withCompound 22 (111 mg, 0.5 mmol). The crude product was purified by flashchromatography on silica gel (gradient elution: 1-3-5% methanol:dichloromethane) to afford 29 mg (17%) of a yellow solid. Example 41: mp258-263° C.; MS (ES⁺ calculated: 337.36; found: 338.15 M+H). HPLC (96%)purity, retention time 11.830 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 13.90 (br s), 10.89 (br s), 10.25 (s), 9.53 (s), 8.96 (s),8.30 (s), 8.14 (m), 7.74 (m), 6.94-9.55 (m), 5.13 (m), 4.91 (m), 3.44(m), 2.22-1.56 (m, 8H).

Example 423-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-4,5-difluoro-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 31 above,4,5-difluorooxindole (Combiblocks, 85 mg, 0.50 mmol) was reacted withCompound 22 (111 mg, 0.5 mmol). The crude product was purified by flashchromatography on silica gel (gradient elution: 1-3-5% methanol:dichloromethane) to afford 94 mg (53%) of a yellow solid. Example 42: mp280-284° C.; MS (ES⁺ calculated: 355.35; found: 356.18 M+H). HPLC (99%)purity, retention time 11.490 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 13.50 (br s), 10.72 (br s), 8.77 (br s), 8.29 (s), 7.05 (m),6.68 (m), 5.00 (m), 2.22-1.50 (m, 8H).

Example 433-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5,7-dinitro-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 31 above,5,7-dinitrooxindole (Combiblocks, 112 mg, 0.506 mmol) was reacted withCompound 22 (111 mg, 0.5 mmol). The crude product was purified by flashchromatography on silica gel (gradient elution: 1-3-5% methanol:dichloromethane) to afford 41 mg (20%) of a yellow solid. Example 43:mp>300° C.; MS (ES⁺ calculated: 409.36; found: 410.19 M+H). HPLC (81%)purity, retention time 12.226 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 11.31 (br s), 9.58 (br s), 9.46 (br s), 8.52 (br s), 8.43 (brs), 7.69 (m), 7.20 (m), 5.02 (m), 4.14 (m), 3.84 (m), 2.33-1.53 (m, 8H).

Example 441-(2-Cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-benzoimidazol-2-one

In a similar fashion as for the preparation of 31 above,2-hydroxybenzimidazole (Acros, 68 mg, 0.506 mmol) was reacted withCompound 22 (111 mg, 0.5 mmol). The crude product was purified by flashchromatography on silica gel (gradient elution: 1-3% methanol:dichloromethane) to afford 47 mg (29%) of a yellow solid. Example 44: mp236-240° C.; MS (ES⁺ calculated: 320.36; found: 321.17 M+H). HPLC (95%)purity, retention time 10.362 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 11.55 (br s), 8.90 (s), 8.86 (s), 8.16 (d, J=8 Hz), 7.19 (m),7.14 (m), 5.18 (m), 2.33-1.58 (m, 8H).

Example 45 3-(2-Cyclohexyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

To 5-cyanooxindole (Combiblocks, 34 mg, 0.21 mmol) in 10 mL anhydroustetrahydrofuran under argon was addedN,N,N′,N′-tetramethylethylenediamine (Acros, 0.06 mL, 0.40 mmol). Thesolution was cooled to −78° C. and lithium diisopropylamide (Acros, 0.21mL of a 2.0M solution in THF/hexane, 0.42 mmol) was added dropwise. Thereaction was stirred for fifteen minutes at which point a solution ofCompound 23 (50 mg, 0.21 mmol) in 10 mL anhydrous tetrahydrofuran wasadded dropwise. The reaction was stirred an additional fifteen minutesand was warmed to room temperature for 0.5 hour. The mixture was thenrefluxed overnight. The reaction was concentrated and subjected to flashchromatography on silica gel (gradient elution: 1-3-5% methanol:dichloromethane) to afford 60 mg (80%) of a yellow solid. Example 45:mp>325° C.; HPLC (97%) purity, retention time 11.957 minutes—Method B);¹H NMR (400 MHz, DMSO-d₆) δ 11.27 (s), 9.57 (s), 9.09 (s), 8.39 (s),8.00 (s), 7.49 (d, J=8 Hz), 7.08 (d, J=8 Hz), 3.40 (m), 2.20-1.20 (m,10H).

Example 465-Bromo-3-(2-cyclohexyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 45 above, 5-bromooxindole(Combiblocks, 45 mg, 0.21 mmol) was reacted with Compound 23 (50 mg,0.21 mmol). The reaction was concentrated and the crude product waspurified by flash chromatography on silica gel (gradient elution: 1-3-5%methanol: dichloromethane) to afford 50 mg (58%) of a brown solid.Example 46: mp 285-290° C.; MS (ES⁺ calculated: 412.29; found: 412.48,414.04 M+H). HPLC (85%) purity, retention time 12.686 minutes—Method B);¹H NMR (400 MHz, DMSO-d₆) δ 11.67 (br s), 10.90 (s), 10.27 (m), 9.57(s), 8.87 (s), 8.60 (s), 8.54 (s), 8.35 (s), 8.19 (m), 7.92 (s), 7.74(s), 7.21 (m), 7.12 (m), 6.89 (m), 6.74 (m), 4.59 (m), 4.37 (m),2.25-1.10 (m, 10H).

Example 473-(2-cyclohexyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-fluoro-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 45 above,5-fluorooxindole (Combiblocks, 32 mg, 0.21 mmol) was reacted withCompound 23 (50 mg, 0.21 mmol). The reaction was concentrated and thecrude product was purified by flash chromatography on silica gel(gradient elution: 1-3-5% methanol: dichloromethane) to afford 39 mg(53%) of a yellow solid. Example 47: mp 294-298° C.; HPLC (88%) purity,retention time 12.604 minutes—Method B); ¹H NMR (400 MHz,trifluoroacetic acid-d) δ 8.72 (s), 8.54 (s), 7.13 (d, J=8 Hz), 6.88(m), 6.78 (m), 3.72 (s), 2.15-0.85 (m, 10H).

Example 485-Chloro-3-(2-cyclohexyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 45 above,5-chlorooxindole (Combiblocks, 35 mg, 0.21 mmol) was reacted withCompound 23 (50 mg, 0.21 mmol). The reaction was concentrated and thecrude product was purified by flash chromatography on silica gel(gradient elution: 1-3-5% methanol: dichloromethane) to afford 22 mg(28%) of an orange-yellow solid. Example 48: mp 294-298° C.; MS (ES⁺calculated: 367.84; found: 368.36 M+H). HPLC (78%) purity, retentiontime 13.406 minutes—Method B); ¹H NMR (400 MHz, trifluoroacetic acid-d)δ 8.97 (s), 8.78 (s), 7.64 (s), 7.18 (d, J=8 Hz), 7.10 (d, J=8 Hz), 4.43(m), 2.30-1.11 (m, 10H).

Example 493-(2-Cyclohexyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitro-1,3-dihydroindol-2-one

In a similar fashion as for the preparation of 45 above, 5-nitrooxindole(Combiblocks, 30 mg, 0.17 mmol) was reacted with Compound 23 (40 mg,0.17 mmol). The reaction was concentrated and the crude product waspurified by flash chromatography on silica gel (gradient elution: 1-3-5%methanol: dichloromethane) to afford 18 mg (28%) of a yellow-brownsolid. Example 49: mp 301-304° C.; MS (ES⁺ calculated: 378.39; found:379.25 M+H). HPLC (100%) purity, retention time 12.798 minutes—MethodB); ¹H NMR (400 MHz, trifluoroacetic acid-d) δ 9.21 (s, 1H), 9.00 (s,1H), 8.73 (s, 1H), 8.42 (s, 1H), 7.52 (s, 1H), 5.28 (s, 1H), 4.62 (m,1H), 2.56-1.11 (m, 10H).

Example 503-(2-cyclohexyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-6-fluoro-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 45 above,6-fluorooxindole (Combiblocks, 32 mg, 0.21 mmol) was reacted withCompound 23 (50 mg, 0.21 mmol). The reaction was concentrated and thecrude product was purified by flash chromatography on silica gel(gradient elution: 1-3-5% methanol: dichloromethane) to afford 22 mg(30%) of an orange solid. Example 50: mp 297-300° C.; MS (ES⁺calculated: 351.39; found: 352.18 M+H). HPLC (89%) purity, retentiontime 12.457 minutes—Method B); ¹H NMR (400 MHz, trifluoroacetic acid-d)δ 9.00 (s, 1H), 8.79 (s, 1H), 7.70 (s, 1H), 6.97 (m, 2H), 4.48 (m, 1H),2.47-1.24 (m, 10H).

Example 516-Chloro-3-(2-cyclohexyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 45 above,6-chlorooxindole (Combiblocks, 35 mg, 0.21 mmol) was reacted withCompound 23 (50 mg, 0.21 mmol). The reaction was concentrated and thecrude product was purified by flash chromatography on silica gel(gradient elution: 1-3-5% methanol: dichloromethane) to afford 19 mg(25%) of an orange solid. Example 51: mp 299-303° C.; MS (ES⁺calculated: 367.84; found: 368.38 M+H). HPLC (97%) purity, retentiontime 13.852 minutes—Method B); ¹H NMR (400 MHz, trifluoroacetic acid-d)δ 9.00 (s, 1H), 8.77 (s, 1H), 7.63 (m, 1H), 7.28 (m, 2H), 4.50 (m, 1H),2.50-1.30 (m, 10H).

Example 523-(2-Cyclohexyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-methoxy-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 45 above,5-methoxyoxindole (36 mg, 0.22 mmol) was reacted with Compound 23 (50mg, 0.21 mmol). The reaction was concentrated and the crude product waspurified by flash chromatography on silica gel (gradient elution: 1-2-3%methanol: dichloromethane) to afford 17 mg (22%) of a yellow solid.Example 52: MS (ES⁺ calculated: 363.42; found: 364.18 M+H). HPLC (62%)purity, retention time 12.048 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 10.54 (s, 1H), 8.88 (s, 1H), 8.29 (s, 1H), 7.26 (s, 2H), 6.83(d, J=8 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 4.56 (m, 1H), 2.20-1.15 (m, 10H).

Example 53 3-(2-Cyclohexyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-trifluoromethyl-1,3-dihydro-indol-2-one

In a similar fashion as for the preparation of 45 above,5-trifluoromethyloxindole (Combiblocks, 44 mg, 0.22 mmol) was reactedwith Compound 23 (50 mg, 0.21 mmol). The reaction was concentrated andthe crude product was purified by flash chromatography on silica gel(gradient elution: 1-5% methanol: dichloromethane) to afford 58 mg (69%)of a yellow solid. Example 53: mp>300° C.; MS (ES⁺ calculated: 401.39;found: 402.20 M+H). HPLC (92%) purity, retention time 14.161minutes—Method B); ¹H NMR (400 MHz, trifluoroacetic acid-d) δ 9.10 (s,1H), 8.84 (s, 1H), 8.03 (s, 1H), 7.68 (s, 1H), 7.40 (s, 1H), 4.50 (m,1H), 2.60-1.23 (m, 10H).

Example 545-Bromo-3-(1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

To 5-bromooxindole (Combi-Blocks, 136 mg, 0.64 mmol) andN,N,N′,N′-tetramethylethylenediamine (Acros, 0.193 mL, 1.28 mmol) in 10mL anhydrous THF under argon at −78° C. was added lithiumdiisopropylamine (Acros, 0.64 mL of a 2.0M solution in THF/heptane, 1.28mmol). The solution was stirred for fifteen minutes at which point asolution of Compound 25 (150 mg, 0.676 mmol) in 10 mL THF was addeddropwise at such a rate as to maintain the temperature below −50° C. Thereaction was stirred for ten minutes, external cooling was removed, andthe reaction was permitted to warm to room temperature. An oil bath wasapplied and the mixture was refluxed for 6 hours. The reaction wasconcentrated. The residue was dissolved in dichloromethane and appliedto flash chromatography on silica gel (gradient elution: 1-3% methanol:dichloromethane). Fractions determined to contain 54 by LC/MS wereconcentrated and dried in vacuo to afford 80 mg (30%) of an orangesolid. Example 54: mp 287-290° C., 270° C. (soft); MS (ES⁺ calculated:398.27; found: 398.39, 399.85 M+H). HPLC (88%) purity, retention time13.496 minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ 14.54 (br s, 1H),10.87 (br s, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 7.80 (s, 1H), 7.20 (d, J=8Hz, 1H), 6.91 (d, J=8 Hz, 1H), 5.25 (m, 1H), 2.12 (m, 2H), 2.02 (m, 2H),1.92 (m, 2H), 1.72 (m, 2H).

Example 553-(1-Cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Using the procedure outlined for 54, 5-cyanooxindole (Combi-Blocks, 116mg, 0.736 mmol) and Compound 25 (172 mg, 0.775 mmol) were refluxedovernight affording 30 mg (11%) of yellow crystals. Example 55: mp>300°C.; MS (ES⁺ calculated: 344.38; found: 345.21 M+H). HPLC (95%) purity,retention time 4.946 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ14.53 (br s, 1H), 11.20 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.01 (s,1H), 7.47 (d, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 5.26 (m, 1H), 2.11 (m,2H), 2.00 (m, 2H), 1.89 (m, 2H), 1.68 (m, 2H).

Example 56 3-(1-Cyclopentyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)-5-trifluoromethyl-1,3-dihydro-indol-2-one

Using the procedure outlined for 54, 5-trifluoromethyloxindole(Combi-Blocks, 68 mg, 0.338 mmol) and Compound 25 (75 mg, 0.338 mmol)were refluxed overnight affording 25 mg (19%) of yellow solid. Example56: mp>300° C.; MS (ES⁺ calculated: 387.37; found: 388.19 M+H). HPLC(96%) purity, retention time 6.279 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 14.50 (br s, 1H), 11.12 (s, 1H), 8.53 (s, 1H), 8.44 (s, 1H),7.93 (s, 1H), 7.40 (d, J=8 Hz, 1H), 7.10 (d, J=8 Hz, 1H), 5.25 (m, 1H),2.22 (m, 2H), 2.11 (m, 2H), 2.01 (m, 2H), 1.81 (m, 2H).

Example 573-(1-Cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-nitro-1,3-dihydro-indol-2-one

Using the procedure outlined for 54, 5-nitrooxindole (Combi-Blocks, 60.2mg, 0.338 mmol) and Compound 25 (75 mg, 0.338 mmol) were refluxedovernight affording 25 mg (20%) of orange solid. Example 57: mp>300° C.(dec); MS (ES⁺ calculated: 364.37; found: 365.19 M+H). HPLC (85%)purity, retention time 5.504 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 14.30 (br s, 1H), 11.40 (s, 1H), 8.55 (m, 2H), 7.99 (d, J=8Hz, 1H), 7.08 (d, J=8 Hz, 1H), 5.29 (m, 1H), 2.13 (m, 2H), 2.02 (m, 2H),1.92 (m, 2H), 1.74 (m, 2H).

Example 585-Chloro-3-(1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Using the procedure outlined for 54, 5-chlorooxindole (Aldrich, 56.6 mg,0.338 mmol) and Compound 25 (75 mg, 0.338 mmol) were refluxed overnightaffording 17 mg (14%) of yellow solid. Example 58: mp 304-306° C.; MS(ES⁺ calculated: 353.81; found: 354.29 M+H). HPLC (94%) purity,retention time 6.119 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ14.59 (br s, 1H), 10.87 (s, 1H), 8.49 (s, 1H), 7.66 (s, 1H), 7.08 (dd,J=2.8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 5.26 (m, 1H), 2.13 (m, 2H), 2.02(m, 2H), 1.91 (m, 2H), 1.72 (m, 2H).

Example 596-Chloro-3-(1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Using the procedure outlined for 54, 6-chlorooxindole (Combi-Blocks,56.6 mg, 0.338 mmol) and Compound 25 (75 mg, 0.338 mmol) were refluxedovernight affording 26 mg (22%) of yellow solid. Example 59: mp 288-291°C.; MS (ES⁺ calculated: 353.81; found: 354.29 M+H). HPLC (99%) purity,retention time 6.017 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ14.61 (br, s, 1H), 10.88 (s, 1H), 8.62 (s, 1H), 8.48 (s, 1H), 7.80 (d,J=8 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 6.93 (s, 1H), 5.24 (m, 1H), 2.12 (m,2H), 2.00 (m, 2H), 1.91 (m, 2H), 1.72 (m, 2H).

Example 603-(1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5,7-dinitro-1,3-dihydro-indol-2-one

Using the procedure outlined for 54, 5,7-dinitrooxindole (Combi-Blocks,100 mg, 0.45 mmol) and Compound 25 (100 mg, 0.45 mmol) were refluxedovernight affording 7 mg (4%) of yellow solid. Example 60: mp 242-246°C.; MS (ES⁺ calculated: 409.36; found: 410.24 M+H). HPLC (95%) purity,retention time 6.416 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ13.15 (br s, 1H), 9.02 (s, 1H), 8.81 (s, 1H), 8.65 (s, 1H), 8.40 (s,1H), 6.95 (s, 1H), 5.36 (m, 1H), 2.18 (m, 2H), 2.05 (m, 2H), 1.92 (m,2H), 1.75 (m, 2H).

Example 613-(1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5,7-difluoro-1,3-dihydro-indol-2-one

Using the procedure outlined for 54, 5,7-difluorooxindole (Oakwood, 76mg, 0.45 mmol) and Compound 25 (100 mg, 0.45 mmol) were refluxedovernight affording 20 mg (13%) of bright yellow solid. Example 61:mp>300° C.; MS (ES⁺ calculated: 355.35; found: 356.17 M+H). HPLC (95%)purity, retention time 5.780 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 14.74 (br s, 1H), 11.23 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H),7.38 (d, J=8 Hz), 6.93 (t, J=8 Hz, 1H) 5.27 (m, 1H), 2.15 (m, 2H), 2.01(m, 2H), 1.93 (m, 2H), 1.73 (m, 2H).

Example 623-(1Cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Using the procedure outlined for 54, oxindole (Combi-Blocks, 59.9 mg,0.45 mmol) and Compound 25 (100 mg, 0.45 mmol) were refluxed overnightaffording 32 mg (22%) of yellow solid. Example 62: mp 228-231° C.; MS(ES⁺ calculated: 319.37; found: 320.16 M+H). HPLC (92%) purity,retention time 5.288 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ14.72 (br s, 1H), 1074 (s, 1H), 8.60 (s, 1H), 8.45 (s, 1H), 7.80 (d, J=8Hz, 1H), 7.02 (m, 2H), 6.93 (d, J=8 Hz, 1H), 5.25 (m, 1H), 2.12 (m, 2H),2.02 (m, 2H), 1.91 (m, 2H), 1.73 (m, 2H).

Example 63 3-(1-Cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile

Using the procedure outlined for 54, 6-cyanooxindole (Combi-Blocks, 80mg, 0.505 mmol) and Compound 25 (111 mg, 0.5 mmol) were refluxedovernight affording 75 mg (44%) of orange solid. Example 63: mp 335-338°C.; MS (ES⁺ calculated: 344.38; found: 345.19 M+H). HPLC (94%) purity,retention time 12.942 minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ11.08 (s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 7.93 (d, J=8 Hz, 1H), 7.40(d, J=8 Hz, 1H), 7.24 (s, 1H), 5.28 (m, 1H), 2.13 (m, 2H), 2.03 (m, 2H),1.91 (m, 2H), 1.72 (m, 2H).

Example 64 3-(1-Cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-7-carbonitrile

Using the procedure outlined for 54, 7-cyanooxindole (Combi-Blocks, 80mg, 0.505 mmol) and Compound 25 (111 mg, 0.5 mmol) were refluxedovernight affording 47 mg (27%) of orange solid. Example 64: mp 327-332°C.; MS (ES⁺ calculated: 344.38; found: 345.18 M+H). HPLC (95%) purity,retention time 13.114 minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ14.58 (br s, 1H), 11.65 (s, 1H), 8.68 (s, 1H), 8.55 (s, 1H), 8.08 (d,J=8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.15 (t, J=8 Hz, 1H), 5.28 (m, 1H),2.13 (m, 2H), 2.02 (m, 2H), 1.91 (m, 2H), 1.72 (m, 2H).

Example 653-(1-Cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-fluoro-1,3-dihydro-indol-2-one

Using the procedure outlined for 54, 5-fluorooxindole (Combi-Blocks, 76mg, 0.503 mmol) and Compound 25 (111 mg, 0.5 mmol) were refluxedovernight affording 25 mg (15%) of orange-yellow solid. Example 65: mp254-257° C.; MS (ES⁺ calculated: 337.36; found: 338.21 M+H). HPLC (80%)purity, retention time 13.366 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 10.77 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 8.05 (s, 1H), 7.48(d, J=10 Hz, 1H), 6.88 (d, J=10 Hz, 1H), 5.26 (m, 1H), 2.12 (m, 2H),2.02 (m, 2H), 1.91 (m, 2H), 1.72 (m, 2H).

Example 663-(1-Cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-6-fluoro-1,3-dihydro-indol-2-one

Using the procedure outlined for 54, 6-fluorooxindole (Combi-Blocks, 76mg, 0.503 mmol) and Compound 25 (111 mg, 0.5 mmol) were refluxedovernight affording 42 mg (25%) of orange-yellow solid. Example 66: mp230-233° C.; MS (ES⁺ calculated: 337.36; found: 338.24 M+H). HPLC (77%)purity, retention time 13.591 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 10.87 (s, 1H), 8.59 (s, 1H), 8.44 (s, 1H), 7.77 (dd, J=5,8Hz, 1H), 6.81 (t, J=9 Hz, 1H), 6.74 (d, J=9 Hz, 1H), 5.24 (m, 1H), 2.11(m, 2H), 2.01 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H).

Example 673-(1-Cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4,5-difluoro-1,3-dihydro-indol-2-one

Using the procedure outlined for 54, 4,5-difluorooxindole (Combi-Blocks,85 mg, 0.503 mmol) and Compound 25 (111 mg, 0.5 mmol) were refluxedovernight affording 27 mg (15%) of yellow solid. Example 67: mp>300° C.;MS (ES⁺ calculated: 355.35; found: 356.20 M+H). HPLC (90%) purity,retention time 13.323 minutes—Method B); ¹H ¹H NMR (400 MHz, DMSO-d₆) δ10.87 (br s, 1H), 8.49 (s, 1H), 8.16 (d, J=8 Hz, 1H), 7.03 (m, 1H), 6.7(m, 1H), 5.22 (m, 1H), 2.09 (m, 2H), 2.00 (m, 2H), 1.89 (m, 2H), 1.70(m, 2H).

Example 68 3-(1-Cyclohexyl-1H-pyrazolo[3,4-de]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

To 5-cyanooxindole (Combi-Blocks, 67 mg, 0.424 mmol) andN,N,N′,N′-tetramethylethylenediamine (Acros, 0.128 mL, 0.848 mmol) in 5mL anhydrous THF under argon at −78° C. was added lithiumdiisopropylamine (Acros, 0.424 mL of a 2.0M solution in THF/heptane,0.848 mmol). The solution was stirred for fifteen minutes at which pointa solution of Compound 26 (100 mg, 0.424 mmol) was added as a solid. Thereaction was stirred for ten minutes, external cooling was removed, andthe reaction was permitted to warm to room temperature. An oil bath wasapplied and the mixture was refluxed overnight. The reaction wasconcentrated. The residue was dissolved in dichloromethane and appliedto flash chromatography on silica gel (gradient elution: 1-3% methanol:dichloromethane). Fractions determined to contain 68 by LC/MS wereconcentrated and the resulting solid was triturated in methanol andfiltered. The solid was dried in vacuo to afford 60 mg (39%) of a yellowsolid. Example 68: mp>300° C.; MS (ES⁺ calculated: 358.41; found: 359.19M+H). HPLC (96%) purity, retention time 5.275 minutes—Method C); ¹H NMR(400 MHz, DMSO-d₆) δ 14.53 (br s, 1H), 11.23 (br s, 1H), 8.69 (s, 1H),8.54 (s, 1H), 8.02 (s, 1H), 7.48 (d, J=9 Hz, 1H), 7.07 (d, J=8 Hz, 1H),4.71 (m, 1H), 1.94 (m, 6H), 1.72 (m, 1H), 1.48 (m, 2H), 1.28 (m, 1H).

Example 693-(1-Cyclohexyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile

Using the procedure outlined for 68, 6-cyanooxindole (Combi-Blocks, 67mg, 0.424 mmol) and Compound 26 (100 mg, 0.424 mmol) were refluxedovernight affording 30 mg (20%) of dark yellow solid. Example 69:mp>300° C.; MS (ES⁺ calculated: 358.41; found: 359.22 M+H). HPLC (98%)purity, retention time 5.526 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 14.77 (br s, 1H), 11.08 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H),7.94 (d, J=8 Hz, 1H), 7.41 (d, J=7 Hz, 1H), 7.24 (s, 1H), 4.73 (m, 1H),1.91 (m, 6H), 1.71 (m, 1H), 1.48 (m, 2H), 1.29 (m, 1H).

Example 70 3-(1-Cyclohexyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-7-carbonitrile

Using the procedure outlined for 68, 7-cyanooxindole (Combi-Blocks, 67mg, 0.424 mmol) and Compound 26 (100 mg, 0.424 mmol) were refluxedovernight affording 27 mg (18%) of yellow solid. Example 70: mp>300° C.;MS (ES⁺ calculated: 358.41; found: 359.28 M+H). HPLC (96%) purity,retention time 5.814 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ14.58 (br s, 1H), 11.65 (s, 1H), 8.67 (s, 1H), 8.55 (s, 1H), 8.08 (d,J=8 Hz, 1 Hz), 7.39 (d, J=8 Hz, 1H), 7.15 (t, J=8 Hz), 4.71 (m, 1H),1.91 (m, 6H), 1.71 (m, 1H), 1.47 (m, 2H), 1.29 (m, 1H).

Example 71 3-(1-Cyclohexyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-trifluoromethyl-1,3-dihydro-indol-2-one

Using the procedure outlined for 68, 5-trifluoromethyloxindole(Combi-Blocks, 85 mg, 0.424 mmol) and Compound 26 (100 mg, 0.424 mmol)were refluxed overnight affording 45 mg (26%) of bright yellow solid.Example 71: mp>300° C.; MS (ES⁺ calculated: 401.39; found: 402.25 M+H).HPLC (93%) purity, retention time 6.578 minutes—Method C); ¹H NMR (400MHz, DMSO-d₆) δ 14.46 (br s, 1H), 11.13 (s, 1H), 8.53 (s, 1H), 8.44 (s,1H), 7.93 (s, 1H), 7.40 (d, J=8 Hz, 1H), 7.11 (d, J=8 Hz, 1H), 4.72 (m,1H), 1.92 (m, 6H), 1.71 (m, 1H), 1.48 (m, 2H), 1.31 (m, 1H).

Example 723-(1-Cyclohexyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-fluoro-1,3-dihydro-indol-2-one

Using the procedure outlined for 68, 5-fluorooxindole (Combi-Blocks, 64mg, 0.424 mmol) and Compound 26 (100 mg, 0.424 mmol) were refluxedovernight affording 50 mg (34%) of yellow solid. Example 72: mp 282-286°C.; MS (ES⁺ calculated: 351.39; found: 352.21 M+H). HPLC (98%) purity,retention time 5.780 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ14.75 (br s, 1H), 1077 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 7.49 (d,J=10 Hz, 1H), 6.89 (m, 2H), 4.70 (m, 1H), 1.90 (m, 6H), 1.71 (m, 1H),1.47 (m, 2H), 1.29 (m, 1H).

Example 733-(1-Cyclohexyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-6-fluoro-1,3-dihydro-indol-2-one

Using the procedure outlined for 68, 6-fluorooxindole (Combi-Blocks, 64mg, 0.424 mmol) and Compound 26 (100 mg, 0.424 mmol) were refluxedovernight affording 15 mg (10%) of bright yellow solid. Example 73: mp277-280° C.; MS (ES⁺ calculated: 351.39; found: 352.18 M+H). HPLC (94%)purity, retention time 5.820 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 14.54 (br s, 1H), 10.87 (s, 1H), 8.59 (s, 1H), 8.44 (s, 1H),7.78 (dd, J=5,8 Hz, 1H), 6.81 (m, 1H), 6.74 (m, 1H), 4.68 (m, 1H), 1.91(m, 6H), 1.71 (m, 1H), 1.49 (m, 2H), 1.28 (m, 1H).

Example 745-Chloro-3-(1-Cyclohexyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Using the procedure outlined for 68, 5-chlorooxindole (Aldrich, 70.4 mg,0.424 mmol) and Compound 26 (100 mg, 0.424 mmol) were refluxed overnightaffording 21 mg (13%) of yellow solid. Example 74: mp 300-305° C.; MS(ES⁺ calculated: 367.84; found: 368.33 M+H). HPLC (97%) purity,retention time 15.299 minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ10.86 (br s, 1H), 8.49 (s, 1H), 8.48 (s, 1H), 7.66 (s, 1H), 7.07 (d, J=8Hz, 1H), 6.93 (d, J=8 Hz, 1H), 4.70 (m, 1H), 1.93-1.28 (m, 10H).

Example 755-Bromo-3-(1-Cyclohexyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Using the procedure outlined for 68, 5-bromooxindole (Combi-Blocks, 89mg, 0.424 mmol) and Compound 26 (100 mg, 0.424 mmol) were refluxedovernight affording 50 mg (29%) of yellow solid. Example 75: mp 305-308°C.; MS (ES⁺ calculated: 412.29; found: 412.51, 413.84 M+H). HPLC (96%)purity, retention time 15.590 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 10.87 (br s, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 7.78 (s, 1H),7.20 (d, J=8 Hz, 1H), 6.90 (d, J=8 Hz, 1H), 4.70 (m, 1H), 2.08-1.25 (m,10H).

Example 763-(2-Allyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

In a similar fashion as for the preparation of 45 above, 5-cyanooxindole(Combiblocks, 60 mg, 0.38 mmol) was reacted with Compound 24 (77 mg,0.40 mmol). The reaction was concentrated and the crude product wastriturated successively with methanol and water. A yellow-orange solidwas obtained which was dried in vacuo. Yield: 67 mg (56%). Example 76:mp>300° C.; MS (ES⁺ calculated: 316.32; found: 317.09 M+H). HPLC (95%)purity, retention time 9.183 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 13.14 (br s), 11.27 (s), 10.81 (br s), 10.63 (br s), 9,54(s), 9.14 (s), 8.77 (br s), 8.40 (s), 8.19 (m), 7.97 (s, 1H), 7.51 (d,J=9 Hz), 7.42 (m), 7.07 (d, J=8 Hz), 6.94 (m), 6.10 (m 1H), 5.29 (m,2H), 5.33-4.94 (m, 2H).

Compound 772-Cyclopentyl-2,7-dihydro-pyrazolo[3,4-d]pyrimidine-4,6-dione

Compound 12 (1 g, 5.15 mmol) was mixed with urea (Fisher, 3 g, 50 mmol)and fused at 200° C. for ninety minutes. The solution was allowed tocool briefly and 10 mL water was added. The solution was boiled for onehour. The white solid present was removed by filtration and wasdetermined to contain additional urea. The solid was recombined with 20mL water and resubjected to boiling for an additional hour. On coolingand filtration, a white solid was obtained which was dried in vacuo.Yield: 837 mg, (74%). Compound 77: mp>300° C.; MS (ES⁺ calculated:220.23; found: 221.17 M+H). HPLC (92%) purity, retention time 5.112minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (br s, 1H), 10.63(br s, 1H), 8.37 (s, 1H), 4.69 (m, 1H), 2.06 (m, 2H), 1.92 (m, 2H), 1.77(m, 2H), 1.63 (m, 2H).

Compound 79 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine

To a mixture of commercially available4-hydroxypyrazolo[3,4-d]pyrimidine (78) (Acros, 14.5 g, 106.5 mmol)stirred in POCl₃ (375 mL) was added N,N-dimethylaniline (21 mL). Themixture was refluxed for 1.5 h. After cooling, excess POCl₃ was removedby rotarty evaporation and pumped on high vacuum before pouring over 500mL ice while stirring. The mixture was stirred for 10 min beforeextracting with ethyl ether (6×250 mL). The combined organic layer waswashed with ice water (3×100 mL) and dried over MgSO₄ and filtered. Theethyl ether was stripped and the resulting pale yellow solid (10 g, 61%)was pumped on high vacuum overnight. Compound 79: mp>300° C., dec. 125°C.; MS (ES⁺ calculated: 154.56; found: 156.21 M+H). HPLC (98% purity,retention time 6.033 minutes—method D) ¹H NMR (400 MHz, DMSO-d₆) δ 14.55(bs, 1H), 8.84 (s, 1H), 8.46 (s, 1H).

Compound 80 4-Chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidine Compound 814-Chloro-1-methyl-2H-pyrazolo[3,4-d]pyrimidine

Cesium carbonate (Acros, 2.12 g, 6.51 mmol) was added to compound 79(1.00 g, 5.9 mmol) in N,N-dimethylformamide (Acros, 30 mL) at 0° C.followed immediately by methyl iodide (Acros, 1.01 g, 7.1 mmol). Themixture was stirred for three hours. Cesium carbonate was removed byfiltration and the filter cake was washed with a small amount of DMF.The filtrate and washings were concentrated and the reaction mixture wassubjected to flash chromatography on silica gel (gradient elution 9:1 to4:1 to 0:1 dichloromethane:ethyl acetate) to afford two white solids:Compound 80 (220 mg, 22%) elutes second and Compound 81 (663 mg, 67%)elutes first. Compound 80: mp 196-200° C.; MS (ES⁺ calculated: 168.59;found: 169.57 M+H). HPLC (100% purity, retention time 4.627minutes—Method B); ¹H NMR (300 MHz, DMSO-d⁶): 8.91 (s, 1H), 8.90 (s,1H), 4.25 (s, 3H). Compound 81: mp 97-99° C.; MS (ES⁺ calculated:168.59; found: 169.37 M+H). HPLC (100% purity, retention time 6.582minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.48 (s,1H), 4.09 (s, 3H).

Example 825-Bromo-3-(2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

5-Bromooxindole (Combiblocks, 63 mg, 0.30 mmol) in 10 mL anhydroustetrahydrofuran (Acros) at −78° C. was treated dropwise with lithiumdiisopropylamide (Acros, 0.3 mL of a 2.0M solution in THF/heptane, 0.60mmol) and the reaction mixture was stirred for fifteen minutes. Compound80 (50 mg, 0.30 mmol) in 5 mL anhydrous tetrahydrofuran was addeddropwise and the reaction was permitted to warm to room temperature overfour hours. The reaction was concentrated and purified by flashchromatography on silica gel (gradient elution, 1-3-5-10-20%methanol:dichloromethane to 1:20:79 ammoniumhydroxide:methanol:dichloromethane) to afford 82 as a yellow solid (81mg, 78%). Example 82: mp 360-5° C., MS (ES⁺ calculated: 344.17; found:345.85 M+H). HPLC (96% purity, retention time 9.548 minutes—Method B);¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s), 9.48 (s), 8.89 (s), 8.34 (s),7.74 (s), 7.22 (d, J=8 Hz), 6.89 (d, J=8 Hz), 4.17 (s, 3H).

Example 835-Chloro-3-(2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Preparation of Example 83: In an identical fashion as for the synthesisof Example 82, Example 83 was prepared as a yellow solid from compound80 in quantitative yield. Example 83: mp 341-4° C., MS (ES⁺ calculated:299.72; found: 300.16 M+H). HPLC (100% purity, retention time 9.323minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s), 9.48 (s), 8.93(s), 8.34 (s), 7.64 (s), 7.09 (d, J=8 Hz), 6.93 (d, J=8 Hz), 4.17 (s,3H).

Example 84 3-(2-Methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

In an identical fashion as for the synthesis of Example 82, Example 84was prepared as a yellow solid from compound 80 in 50% yield. Example84: mp>350° C., MS (ES⁺ calculated: 290.29; found: 291.07 M+H). HPLC(100% purity, retention time 7.467 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 11.27 (s), 9.49 (s), 9.11 (s), 8.39 (s), 7.99 (s), 7.50 (d,J=8 Hz), 7.08 (d, J=8 Hz), 4.19 (s, 3H).

Example 855-Bromo-3-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

In an identical fashion as for the synthesis of 82, Example 85 wasprepared as a yellow solid from compound 81 in 20% yield. Example 85:mp>350° C., MS (ES⁺ calculated: 344.17; found: 345.86 M+H). HPLC (95%purity, retention time 11.124 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 10.91 (s), 8.51 (s), 8.43 (s), 7.77 (s), 7.20 (d, J=8 Hz),6.90 (d, J=8 Hz), 3.99 (s, 3H), 3.93 (s).

Example 865-Chloro-3-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

In an identical fashion as for the synthesis of 82, Example 86 wasprepared as a yellow solid from compound 81 in 49% yield. Example 86:mp>320° C., MS (ES⁺ calculated: 299.72; found: 300.09 M+H). HPLC (99%purity, retention time 10.772 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 10.90 (s), 8.52 (s), 8.47 (s), 7.65 (s), 7.08 (d, J=8 Hz),6.94 (d, J=8 Hz), 3.99 (s, 3H), 3.93 (s).

Compound 87 and 882-(propyl-3-azido)-4-Chloro-2H-pyrazolo[3,4-d]pyrimidine1-(propyl-3-azido)-4-Chloro-1H-pyrazolo[3,4-d]pyrimidine

In an identical fashion as for the alkylation of 79 with iodomethane,Compound 87 and Compound 88 were prepared as yellow solids in 10% and40% yields, respectively. Compound 87: MS (ES⁺ calculated: 237.65;found: 238.29 M+H). HPLC (100% purity, retention time 7.76minutes—Method B); ¹H NMR (300 MHz, DMSO-d⁶): 8.84 (s, 1H), 8.31 (s,1H), 4.64 (t, J=7 Hz, 2H), 3.42 (t, J=7 Hz, 2H), 2.35 (t, J=7 Hz, 2H).Compound 88: MS (ES⁺ calculated: 237.65; found: 238.02 M+H). HPLC (99%purity, retention time 10.002 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 8.88 (s, 1H), 8.51 (s, 1H), 4.55 (t, J=7 Hz, 2H), 3.38 (t,J=7 Hz, 2H), 2.13 (t, J=7 Hz, 2H).

Example 893-[2-(3-azido-propyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-bromo-1,3-dihydro-indol-2-one

In an identical fashion as for the preparation of Example 82, Compound87 was alkylated to produce Example 89 in 91% yield. Compound 89: mp252-6° C., MS (ES⁺ calculated: 413.24; found: 414.87 M+H). HPLC (97%purity, retention time 11.337 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 0.90 (s), 9.53 (s), 8.93 (s), 8.34 (s), 7.75 (s), 7.22 (d,J=8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 4.53-4.38 (m, 2H), 3.44-3.38 (m, 2H),2.17-2.11 (m, 2H).

Example 903-[2-(3-methylamino-propyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-bromo-1,3-dihydro-indol-2-one

Example 89 (20 mg, 48.4 μmol) was suspended in 5 mL anhydrous1,2-dichloroethane (Acros) and treated with bromodimethylborane (Acros,5 μL, 50 μmol). The mixture was stirred overnight. Additionalbromodimethylborane (in 50 μmol aliquots) was added on three occasionsover three days with a drop of N-methylpyrrolidinone (Acros, anhydrous)being added on each occasion to promote solubility. The reaction wasconcentrated and ethanol was added (5 mL). The reaction was stirred tenminutes and reconcentrated. The solid was taken up into a small amountof methanol (approximately 1-2 mL) and dichloromethane was added toturbidity. The solution was allowed to sit for several hours and ayellow solid was isolated by filtration. The solid was washed with asmall amount of anhydrous dichloromethane and was dried in vacuo. Yield:12 mg (51%) of the hydrobromide salt. Example 90: mp 240-3° C., MS (ES⁺calculated: 401.27; found: 402.90 M+H). HPLC (87% purity, retention time8.813 minutes—Method A); ¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s), 9.537(s), 8.92 (s), 8.36 (s), 7.75 (s), 7.23 (m), 7.14 (m), 6.90 (m), 6.77(m), 4.55-4.42 (m), 2.92 (m), 2.51 (m), 2.32-2.18 (m).

Compound 91 and 92 4-Chloro-1-propyl-1H-pyrazolo [3,4-d]pyrimidine4-Chloro-2-propyl-1H-pyrazolo [3,4-d]pyrimidine

Cs₂CO₃ was added to a solution of 79 (2.0 g, 13 mmol) in 60 mL anhydrousDMF at 0° C. 1-Iodopropane (Acros, 1.52 mL, 15.6 mmol) was added to thesuspension and allowed to stir for 3.5 h at 0° C. The reaction mixturewas filtered and the solid was washed with dichloromethane. The filtratewas concentrated to dryness and the residue was dissolved in 9:1hex/EtOAc and applied to flash chromatography on silica gel (gradientelution: 9:1, 4:1, 0:1 hexane:ethylacetate). Fractions determined tocontain 91 and 92 by LC/MS were concentrated to afford 830 mg (33%) ofclear colorless oil 91 and 296 mg (12%) yellow solid 92. Compound 91: MS(ES⁺ calculated: 196.64; found: 197.09 M+H). HPLC (100% purity,retention time 10.314 minutes—method D) ¹H NMR (300 MHz, DMSO-d⁶): 8.87(s, 1H), 8.48 (s, 1H), 4.45 (t, J=7 Hz, 2H), 1.91 (m, 2H), 0.85 (t, J=7,3H). Compound 92: mp 93-95° C.; MS (ES⁺ calculated: 196.64; found:197.09 M+H). HPLC (90% purity, retention time 7.931 minutes—method D) ¹HNMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.53 (s, 1H), 4.37 (t, J=7, 2H),1.92 (m, 2H), 0.83 (t, J=7, 3H).

Example 933-(1-propyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

5-cyanooxindole (Combiblocks, 161 mg, 1.02 mmol) in 5 mL anhydroustetrahydrofuran was stirred under argon. The solution was cooled to −78°C. and lithium diisopropylamide (Acros, 1.02 mL of a 2.0M solution inTHF/hexane, 2.04 mmol) was added dropwise. The reaction was stirred forfifteen minutes at which point Compound 91 (200 mg, 1.02 mmol) wasadded. The reaction was stirred an additional fifteen minutes and waswarmed to room temperature over 0.5 hour. The mixture was then stirredovernight at room temperature. The reaction was concentrated andsubjected to flash chromatography on silica gel (gradient elution:1-3-5% methanol: dichloromethane) to afford 30 mg (9%) of a yellow solidafter trituration in MeOH. Example 93: mp>300° C.; MS (ES⁺ calculated:318.34; found: 319.18 M+H). HPLC (99%) purity, retention time 4.068minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ 11.25 (s, 1H), 8.71 (s,1H), 8.55 (s, 1H), 8.02 (s, 1H), 7.48 (d, J=8, 1H), 7.07 (d, J=8, 1H),4.35 (t, 2H), 1.88 (m, 2H), 0.87 (t, J=7, 3H).

Example 945-Bromo-3-(1-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 93, 5-bromooxindole(Combiblocks, 108 mg, 0.51 mmol) and Compound 91 (100 mg, 0.51 mmol)were stirred overnight to afford 86 mg (45%) of a yellow solid. Example94: mp 295-300° C.; MS (ES⁺ calculated: 372.23; found: 372.47 M+H). HPLC(99%) purity, retention time 5.243 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 14.58 (s), 10.90 (s, 1H), 8.51 (s, 1H), 8.45 (s, 1H), 7.78(s, 1H), 7.20 (d, 1H), 6.90 (d, J=8, 1H), 4.33 (t, 2H), 1.88 (m, 2H),0.87 (t, J=7, 3H).

Example 955-Chloro-3-(1-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 93, 5-chlorooxindole(Combiblocks, 85.5 mg, 0.51 mmol) and Compound 91 (100 mg, 0.51 mmol)were stirred overnight to afford 62 mg (37%) of a yellow solid. Example95: mp 293-297° C.; MS (ES⁺ calculated: 327.78; found: 328.28 M+H). HPLC(99%) purity, retention time 5.056 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 14.61 (s), 10.89 (s, 1H), 8.49 (d, J=7, 2H), 7.65 (s, 1H),7.08 (d, J=8, 1H), 6.93 (d, J=8), 4.33 (t, J=7, 2H), 1.88 (m, 2H), 0.87(t, J=7, 3H).

Example 963-(2-propyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

5-cyanooxindole (Combiblocks, 40.4 mg, 0.255 mmol) in 1.5 mL anhydroustetrahydrofuran was stirred under argon. The solution was cooled to −78°C. and lithium diisopropylamide (Acros, 0.255 mL of a 2.0M solution inTHF/hexane, 0.51 mmol) was added dropwise. The reaction was stirred forfifteen minutes at which point Compound 92 (50 mg, 0.255 mmol) wasadded. The reaction was stirred an additional fifteen minutes and waswarmed to room temperature over 0.5 hour. The mixture was then stirredovernight at room temperature. The reaction was concentrated andsubjected to flash chromatography on silica gel (gradient elution:1-3-5% methanol: dichloromethane) to afford 18 mg (22%) of a yellowsolid after trituration in MeOH. Example 96: mp>300° C.; MS (ES⁺calculated: 318.34; found: 319.14 M+H). HPLC (98%) purity, retentiontime 3.532 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ 11.25 (s),9.52 (s), 9.13 (s), 8.40 (s), 7.98 (s), 7.49 (d), 7.09 (d), 4.40 (m),4.36 (bs), 4.10 (bs), 1.90 (m), 0.88 (m).

Example 975-Bromo-3-(2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Using the procedure outlined for 96, 5-bromooxindole (Combiblocks, 54mg, 0.255 mmol) and Compound 92 (50 mg, 0.255 mmol) were stirredovernight to afford 35 mg (37%) of an orange solid. Example 97: mp>300°C.; MS (ES⁺ calculated: 372.23; found: 373.79 M+H). HPLC (98%) purity,retention time 4.271 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ14.09 (s), 10.89 (s), 9.50 (s). 8.90 (s), 8.34 (s), 7.73 (s), 7.23 (d),6.90 (d), 4.41 (t, J=7), 1.93 (m), 0.86 (m).

Example 985-Chloro-3-(2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Using the procedure outlined for 96, 5-chlorooxindole (Combiblocks, 42.7mg, 0.255 mmol) and Compound 92 (50 mg, 0.255 mmol) were stirredovernight to afford 55 mg (66%) of a yellow solid. Example 98: mp302-306° C.; MS (ES⁺ calculated: 327.78; found: 328.27 M+H). HPLC (98%)purity, retention time 4.145 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 10.88 (s), 9.52 (s), 8.95 (s), 8.35 (s), 7.62 (s), 7.10 (d),6.95 (d), 4.42 (t, J=7), 1.93 (m), 0.90 (m).

Example 993-(1-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-trifluoromethyl-1,3-dihydro-indol-2-one

Using the procedure outlined for 96, 5-trifluoromethyloxindole(Combiblocks, 36 mg, 0.179 mmol) and Compound 92 (35 mg, 0.179 mmol)were stirred overnight to afford 35 mg (54%) of a white solid. Example99: mp 293-295° C.; MS (ES⁺ calculated: 361.33; found: 362.17 M+H). HPLC(98%) purity, retention time 4.145 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 11.12 (s), 9.53 (s), 8.85 (s), 8.35 (d), 8.06 (t), 7.87 (s),7.40 (d), 7.10 (d), 4.23 (m), 1.87 (m), 0.87 (m).

Example 1003-(1-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-fluoro-1,3-dihydro-indol-2-one

Using the procedure outlined for 96, 5-fluorooxindole (Combiblocks, 27mg, 0.179 mmol) and compound 92 (35 mg, 0.179 mmol) were stirredovernight to afford 30 mg (54%) of a yellow solid. Example 100: mp288-292° C.; MS (ES⁺ calculated: 311.32; found: 312.13 M+H). HPLC (93%)purity, retention time 3.762 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 14.32 (s), 10.79 (s), 9.03 (s), 8.34 (s), 7.50 (d, J=10),6.91 (s), 4.42 (s), 1.92 (s), 0.89 (m).

Compounds 101 and 102 3-Amino-1-propyl-1H-pyrazole-4-carbonitrile5-Amino-1-propyl-1H-pyrazole-4-carbonitrile

3-Amino-4-pyrazolecarbonitrile 1 (Acros, 3.24 g, 30.0 mmol),propylbromide (Acros, 4.43 g, 36 mmol) and anhydrous potassium carbonate(Fisher, 5.0 g, 36 mmol) were suspended in 20 mL anhydrous DMF andheated at 80° C. in a sealed tube under argon overnight. The reactionwas permitted to cool and the DMF was removed on a rotary evaporator.Water was added (100 mL) and the organics were extracted withdichloromethane (3×100 mL). The combined dichloromethane fractions werewashed with water (50 mL) and brine (50 mL) and were dried (magnesiumsulfate). Concentration of the organics afforded an oil which wassubjected to flash chromatography on silica gel (1-3%methanol/dichloromethane). Two white crystals were obtained: compound101 (1.88 g, 42%) elutes first and compound 102 (711 mg, 16%) elutessecond. Compound 101: mp 85-90° C.; MS (ES⁺ calculated: 150.18; found:151.15 M+H). HPLC (99%) purity, retention time 5.8 minutes—Method A); ¹HNMR (400 MHz, DMSO-d₆) δ 8.07 (s, 1H), 5.52 (s, 2H), 3.82 (t, J=7, 2H),1.70 (m, 2H), 0.79 (t, J=7, 3H). Compound 102: mp 162-164° C.; MS (ES⁺calculated: 150.18; found: 151.18 M+H). HPLC (95%) purity, retentiontime 6.4 minutes—Method A); ¹H¹H NMR (400 MHz, DMSO-d₆) δ 7.51 (s, 1H),6.53 (s, 2H), 3.82 (t, J=7, 2H), 2.95 (m, 2H), 0.81 (t, J=7, 3H).

Compound 103 3-Amino-1-propyl-1H-pyrazole-4-carboxylic acid amide

To concentrated sulfuric acid (Fisher, 1.5 mL) at 0° C. was added 101(931 mg, 6.21 mmol). The reaction was permitted to warm to roomtemperature and was stirred for three hours. At the end of this periodall solid had dissolved. This viscous mixture was then added slowly(violent) to 15 mL concentrated ammonium hydroxide solution (Fisher).The mixture was stirred for ten minutes and the white solid that formedwas collected by filtration, was washed with water, and was dried invacuo. The filtrate was also concentrated, triturated in water andfiltered. Both white crystal solids were compound 103. Yield: 850 mg(82%). Compound 103: mp 160-163° C.; MS (ES⁺ calculated: 168.20; found:169.31 M+H). HPLC (99% purity, retention time 5.358 minutes—Method D);¹H NMR (400 MHz, DMSO-d₆) δ 7.86 (s, 1H), 7.18 (bs, 1H), 6.70 (bs, 1H),5.33 (s, 2H), 3.78 (t, J=7, 2H), 1.70 (m, 2H), 0.81 (t, J=7, 3H).

Compound 104 2-Propyl-2H-pyrazolo[3,4-d]pyrimidine-4,6-diol

Compound 103 (510 mg, 3.03 mmol) and urea (Fisher, 1.5 g, 25 mmol) weremelted at 200° C. with stirring. After 1.5 h the reaction was allowed tocool to 100° C. when 10 mL water was added and the reaction mixture wasboiled overnight. The mixture was cooled and filtered followed by waterwash. The white solid was dried in vacuo to afford 412 mg (70%) ofcompound 104. Compound 104: mp>300° C.; MS (ES⁺ calculated: 194.19;found: 195.19 M+H). HPLC (99% purity, retention time 5.828minutes—Method D); ¹H NMR (400 MHz, DMSO-d₆) δ 11.34 (s, 1H), 10.66 (s,1H), 8.33 (s, 1H), 4.05 (t, J=7, 2H), 1.78 (m, 2H), 0.82 (t, J=7, 3H).

Compound 105 4,6-Dichloro-2-propyl-1H-pyrazolo[3,4-d]pyrimidine

A mixture of commercially available4,6-dihydroxypyrazolo[3,4-d]pyrimidine 104 (Acros, 400 mg, 2.06 mmol)stirred in POCl₃ (10 mL) was refluxed overnight. After cooling, excessPOCl₃ was removed by rotarty evaporation and pumped on high vacuumbefore adding ice chips while stirring. The mixture was stirred for 10min before the white precipitate was filtered and dried in vacuo. Yield407 mg (85%). Compound 105: mp 80-84° C.; MS (ES⁺ calculated: 232.10;found: 233.00 M+H). HPLC (99%) purity, retention time 10.091minutes—method D) ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (s, 1H), 4.46 (t,J=7, 2H), 1.95 (m, 2H), 0.85 (t, J=7, 3H).

Compound 107 4,6-Dichloro-5-[1,3]dioxolan-2-yl-pyrimidine

A mixture of 300 ml benzene and 8.2 ml ethylene glycol was heated toreflux and 100 ml solution was distilled off. To the hot solution wasadded 4,6-dichloro-5-pyrimidinecarbaldehyde (Bionet, 8.6 g, 48.6 mmol)and p-toluenesulfonic acid monohydrate (Aldrich, 150 mg, 0.8 mmol). Themixture was returned to reflux and water was removed via Dean-Stark trapover 3 h. After cooling, the solvents were removed under vacuum to yielda dry, yellow solid. The solids were slurried in H₂O (30 ml)/saturatedNaHCO₃ solution (30 ml). White solid 107 was filtered off and driedunder vacuum (8.8 g, 82%). Compound 107: mp 108-110° C.; MS (ES⁺calculated: 221.04; found: 221/223 M+H). ¹H NMR (400 MHz, DMSO-d₆) δ8.95 (s, 1H), 6.26 (s, 1H), 4.23 (m, 2H), 4.05 (m, 2H).

Example 1083-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

A solution of 5-cyanooxindole (Combiblocks, 31.6 mg, 0.2 mmol) in 2 mLanhydrous tetrahydrofuran under argon was cooled to −78° C. and lithiumdiisopropylamide (Acros, 0.2 mL of a 2.0M solution in THF/hexane, 0.4mmol) was added dropwise. The reaction was stirred for fifteen minutesat which point a solution of compound 107 (46.8 mg, 0.21 mmol) in 2 mLanhydrous tetrahydrofuran was added dropwise. The reaction was stirredan additional fifteen minutes and was warmed to room temperature for 1hour. The orange solution was quenched with methylhydrazine (1000 andstirred at ambient temperature 16 h. The solvents were removed undervacuum and methanol (1 ml) was added to the solids. After 10 min. ofstirring, the tan solids were filtered off (5.0 mg, 8.6%). Example 108:mp>300° C. (dec); MS (ES⁺ calculated: 290.29; found: 291 M+H). ¹H NMR(400 MHz, DMSO-d₆) δ 14.59 (br s, 1H), 11.27 (s, 1H), 8.70 (s, 1H), 8.56(s, 1H), 8.01 (s, 1H), 7.48 (d, J=8.6 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H),4.01 (s, 3H).

Example 1092-Oxo-3-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2,3-dihydro-1H-indole-5-carbonitrile

A solution of 5-cyanooxindole (Combiblocks, 79.0 mg, 0.5 mmol) in 5 mLanhydrous tetrahydrofuran under argon was cooled to −78° C. and lithiumdiisopropylamide (Acros, 0.5 mL of a 2.0M solution in THF/hexane, 1.0mmol) was added dropwise. The reaction was stirred for fifteen minutesat which point a solution of compound 107 (113 mg, 0.53 mmol) in 5 mLanhydrous tetrahydrofuran was added dropwise. The reaction was stirredan additional fifteen minutes and was warmed to room temperature for 1hour. The orange solution was quenched with hydrazine monohydrate (120μl) and stirred at ambient temperature 24 h, then at reflux for 16 h.The solvents were removed under vacuum and methanol (1 ml) was added tothe solids. After 10 min. of stirring, the tan solids were filtered off.Methanol addition and filtration was repeated 3 times to give a darkbrown solid (21 mg, 15%). Example 109: mp>300° C. (dec); MS (ES⁺calculated: 276.26; found: 277 M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 14.29(br s), 11.57 (s), 11.25 (s), 10.01 (br s), 9.45 (s), 9.27 (s), 8.70(m), 8.50 (s), 8.37 (s), 8.02 (s), 7.82 (s), 7.47 (d, J=9 Hz), 7.06 (d,J=8 Hz), 6.79 (m).

Compound 110 4-Chloro-2-pentyl-2H-pyrazolo[3,4-d]pyrimidine

To a suspension of 79 (3.00 g, 19.41 mmol) and CsCO₃ (6.95 g, 21.34mmol) in 50 mL of anhydrous DMF was charged pentyliodide (3.04 mL, 23.29mmol) drop wise with a syringe. Allow reaction to stir at roomtemperature for 36 h. After filtering the solids, the remaining DMF wasconcentrated in vacuo. The residue was resuspended in water anddichloromethane, the layers separated and the aqueous layer extractedwith 2×20 mL portions of dichlormethane. The combined organic was driedover MgSO₄, filtered and concentrated in vacuo. The resulting reddishsolid was purified via column chromatography on 150 g SiO₂, elutedsequentially with the following concentrations of ethyl acetate indichloromethane:10%, 20%, 50%, 100%. The most polar eluted compound wascollected, stripped to a brown oily solid, (189 mg, 4.3%) and used inthe next reaction. MS (m/e) 225 (M+1).

Example 1113-(2-pentyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile

To the 5-cyanooxindole 110 (71 mg, 0.45 mmol) in 2 mL of anhydrous THFstirring at −78° C., was added LDA (Acros 2.0 m in THF/n-pentane, 5604,1.125 mmol) drop wise with a syringe. The anionic solution was stirredat −78° C. for 45 minutes. To the solution was added the isolated4-chloropyrazolo-2-n-pentyl[3,4-d]pyrimidine in 1 mL anhydrous THF. Thesolution was stirred at −78° C. for 1 hour and then allowed to warm andstir at room temperature for 2 hours. The reaction was quenched with 2mL of saturated NH₄Cl, transferred to a separatory funnel andpartitioned between dichloromethane and water. After extracting thewater layer with 2×20 mL portions of dichloromethane, the combinedorganic was dried over MgSO₄, filtered and concentrated in vacuo. Theresulting residue was purified via flash chromatography on 60 g SiO₂,and eluted with 5% methanol in dichloromethane yielding a yellow solid(44 mg, 28%). Example 111: mp=290° C. dec., ¹H NMR (400 MHz, DMSO-d₆) δ11.25 (s, 1H), 9.50 (s, 1H), 9.10 (s, 1H), 8.35 (d, J=4 Hz), 7.95 (s,1H), 7.5 (d, J=8 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 4.45 (t, J=7 Hz, 1H),4.20 (t, J=7 Hz, 1H), 1.90 (m, 2H), 1.3 (m, 4H), 0.85 (t, J=7 Hz, 3H);MS m/e 347 (M+1), HPLC (99% purity, retention time 9.82 minutes, methodB).

Compound 112 4,6-Dichloro-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrmidine

To a 50 mL flask was added compound 77 (500 mg, 2.27 mmol) and POCl₃ (8mL) and the mixture was heated to reflux for 1.5 h. After cooled to roomtemperature, the reaction was concentrated in vacuo. The residue wasquenched with ice-water (30 mL) and basified with NaOH (10 N) solutionto pH 9. The precipitation was filtered and washed with water, dried togive 504 mg (86%) of the desired compound 112. Compound 112: ¹H NMR (400MHz, DMSO-d₆) δ 9.10 (s, 1H), 5.11 (m, 1H), 2.22-1.71 (m, 8H); MS (m/e)257 (M+1).

Example 1133-(6-Chloro-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

To a stirring solution of 5-cyanooxindole (435 mg, 2.75 mmol) and THF(25 mL) in 125 mL flask at −78° C. was added LDA (3.5 mL, 7.0 mmol).After the reaction was stirred for 45 min, a solution of compound 112(707 mg, 2.75 mmol) in THF (5 mL×2) was added and continued to stir for1 h at −78° C. The reaction was allowed to warm to room temperature andstirred for additional 2 h. It was quenched with water (30 mL) and wasacidified to pH 2 with concentrated HCl. The resulting precipitate wasfiltered, washed with water, and dried under house vacuum at 50° C.overnight to give 551 mg (53%) of the desired product Example 113.Example 113: ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 9.41 (s, 1H),8.41 (s, 1H), 7.45 (d, 1H), 6.97 (d, 1H), 5.01 (m, 1H), 2.19-1.69 (m,9H); −MS (m/e) 379 (M+1).

Example 113A 5-Chloro-3-(6-chloro-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 9.34 (s,1H), 8.10 (s, 1H), 7.05 (m, 1H), 6.83 (m, 1H), 4.99 (s, 1H), 2.18-1.69(m, 9H); −MS (m/e) 388 (M+1).

Scheme 3 discloses a general procedure for the preparation of compoundsof Formula XI. To a reaction vessel can be added a compound of FormulaX, about 10 equivalents of a compound of formula NHR⁹R¹⁰, and2-methoxyethanol. The reaction mixture can be heated to reflux for about6 to 7 hours. The reaction when complete can be cooled to roomtemperature, can be concentrated and the residue can be purified bycolumn chromatography to give the desired product.

Example 1143-(2-cyclopentyl-6-(2-pyridin-3-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

To a Carousel tube was added Example 113 (200 mg, 0.528 mmol),3-(2-aminoethyl)pyridine (645 mg, 5.28 mmol), and 2-methoxyethanol (8mL). The reaction mixture was heated to reflux for 6.5 h. After cooledto room temperature, the reaction was concentrated and the residue waspurified by Biotage (CH₂Cl₂/MeOH 10:1) to give 204 mg (83%) the desiredproduct. Example 114: ¹H NMR (400 MHz, DMSO-d₆) δ 11.63 (s, 1H), 10.39(s, 1H), 9.50 (s, 1H), 8.72 (s, 1H), 8.51 (s, 1H), 8.43 (m, 1H), 7.74(m, 1H), 7.34-7.28 (m, 2H), 6.86 (m, 1H), 4.83 (m, 1H), 3.77 (s, 2H),3.00 (m, 2H), 2.17-1.67 (m, 9H); MS (m/e) 465 (M+1).

The following Examples 115-144 in Table 1 were prepared according toprocedures disclosed herein, using the appropriate starting materials,including the general procedure for the preparation of compounds ofFormula XI, disclosed herein, displacement of halogens by amines,alcohols or water, and/or using methods generally known to one skilledin the art.

TABLE 1

Example R² —X 115 —CN CH₃NH— 116 —CN CH₃CH₂CH₂CH₂NH— 117 —CN

118 —CN

119 —CN

120 —CN —OH 121 —CN

122 —CN

123 —CN

124 —CN NH₂NH— 125 —CN

126 —CN

127 —CN

128 —CN

129 —CN

130 —CN

131 —CN

132 —CN

133 —CN

134 —CN

135 —CN

136 —CN

137 —CN

138 —CN

139 —CN

140 —Cl

141 —Cl

142 —Cl CH₃NH— 143 —Cl

144 —Cl

Example 1153-(2-cyclopentyl-6-methylamino-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 11.70 (s, 1H), 10.37 (s,1H), 9.49 (s, 1H), 8.75 (s, 1H), 7.28 (m, 1H), 6.85 (m, 1H), 4.83 (m,1H), 3.01 (s, 3H), 2.13-1.68 (m, 9H); MS (m/e) 374 (M+1).

Example 116 3-(6-butylamino-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.48 (s,1H), 8.69 (s, 1H), 7.27 (m, 1H), 6.85 (m, 1H), 4.82 (m, 1H), 3.46 (s,2H), 2.13-1.44 (m, 13H), 0.94 (m, 4H); MS (m/e) 416 (M+1).

Example 1173-(2-cyclopentyl-6-(4-methyl-piperazin-1-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.47 (s,1H), 8.49 (s, 1H), 7.25 (m, 1H), 6.85 (m, 1H), 4.85 (m, 1H), 3.84 (m,3H), 2.60 (s, 4H), 2.34-1.68 (m, 13H); MS (m/e) 443 (M+1).

Example 1183-(2-cyclopentyl-6-morpholin-4-yl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 9.49 (s,1H), 8.47 (s, 1H), 7.30 (m, 1H), 6.87 (m, 1H), 4.87 (m, 1H), 3.78 (m,8H), 2.15-1.69 (m, 9H); MS (m/e) 430 (M+1).

Example 119 3-(2-cyclopentyl-6-(2-dimethylamino-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 9.48 (s,1H), 8.68 (s, 1H), 7.25 (m, 1H), 6.84 (m, 1H), 4.80 (m, 1H), 3.57 (s,2H), 2.65 (s, 2H), 2.31 (s, 6H), 2.15-1.68 (m, 10H); MS (m/e) 431 (M+1).

Example 120 3-(2-cyclopentyl-6-hydroxy-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 12.92 (s, 1H), 11.83 (s,1H), 11.33 (s, 1H), 8.93 (s, 1H), 7.95 (s, 1H), 7.53 (m, 1H), 7.07 (m,1H), 5.05 (m, 1H), 2.14-1.69 (m, 8H)

Example 1213-{2-cyclopentyl-6-[(2-diethylamino-ethyl)-methyl-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.22 (s, 1H), 9.47 (s,1H), 8.61 (s, 1H), 7.19 (m, 1H), 6.82 (m, 1H), 4.80 (m, 1H), 3.78 (s,2H), 3.33 (s, 3H), 2.99 (s, 2H), 2.85 (s, 4H), 2.12-1.68 (m, 9H), 1.12(s, 6H); MS (m/e) 473 (M+1).

Example 1223-[2-cyclopentyl-6-(2-dimethylamino-ethoxy)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 11.81 (s, 1H), 10.41 (s,1H), 9.45 (m, 1H), 8.53 (s, 1H), 7.29 (m, 1H), 6.86 (m, 1H), 4.86 (m,1H), 3.82 (s, 4H), 2.15-1.67 (m, 14H).

Example 1233-{2-cyclopentyl-6-[(pyridin-2-yl-methyl)amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.48 (s,1H), 8.57 (s, 1H), 7.76 (m, 2H), 7.41 (m, 1H), 7.26 (m, 2H), 6.83 (m,1H), 4.83 (m, 3H), 2.13-1.68 (m, 10H); MS (m/e) 451 (M+1).

Example 124 3-(2-cyclopentyl-6-hydrazino-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H), 9.50 (s,1H), 9.36 (s, 1H), 8.82 (s, 1H), 7.24 (m, 1H), 6.82 (m, 1H), 4.82 (m,1H), 2.16-1.68 (m, 11H); MS (m/e) 375 (M+1).

Example 125 3-[2-cyclopentyl-6-(2-pyridin-2-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 9.49 (s,1H), 8.73 (s, 1H), 8.54 (m, 1H), 7.73 (m, 1H), 7.37-7.23 (m, 4H), 6.86(m, 1H), 4.83 (m, 1H), 3.89 (s, 2H), 3.16 (m, 2H), 2.15-1.67 (m, 9H); MS(m/e) 465 (M+1).

Example 126 3-(2-cyclopentyl-6-(2-pyridin-4-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 9.50 (s,1H), 8.48 (m, 3H), 7.33 (m, 4H), 6.86 (m, 1H), 4.83 (m, 1H), 3.78 (s,2H), 3.01 (s, 2H), 2.15-1.68 (m, 9H); MS (m/e) 465 (M+1).

Example 1273-{2-cyclopentyl-6-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 9.41 (s,1H), 8.53 (s, 1H), 7.11 (m, 1H), 6.79 (m, 1H), 4.77 (m, 1H), 3.84 (s,5H), 3.03 (m, 6H), 2.58 (s, 6H), 2.11-1.68 (m, 12H); MS (m/e) 526 (M+1).

Example 1283-{2-cyclopentyl-6-[4-(3-phenyl-propyl)-piperazin-1-yl]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 9.47 (s,1H), 8.50 (s, 1H), 7.28-7.17 (m, 6H), 6.86 (m, 1H), 4.84 (m, 1H), 3.84(s, 4H), 2.65 (m, 6H), 2.42 (s, 2H), 2.15-1.67 (m, 11H); MS (m/e) 547(M+1).

Example 1293-{2-cyclopentyl-6-[4-(2-pyridin-2-yl-ethyl)-piperazin-1-yl]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 9.48 (s,1H), 8.48 (m, 2H), 7.71 (m, 1H), 7.69 (m, 2H), 7.20 (m, 1H), 6.86 (m,1H), 4.86 (m, 1H), 3.83 (s, 4H), 2.96 (s, 2H), 2.70 (m, 6H), 2.17-1.69(m, 9H); MS (m/e) 534 (M+1).

Example 1303-{2-cyclopentyl-6-[4-(2-thiophen-2-yl-ethyl)-piperazin-1-yl]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 10.43 (s,1H), 9.48 (s, 1H), 8.51 (s, 1H), 7.31 (m, 2H), 6.96-6.86 (m, 2H), 4.86(m, 1H), 3.85 (s, 4H), 3.03 (s, 2H), 2.65 (s, 6H), 2.17-1.69 (m, 9H); MS(m/e) 539 (M+1).

Example 1313-(2-cyclopentyl-6-piperidin-1-yl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 10.42 (s,1H), 9.47 (s, 1H), 8.54 (s, 1H), 7.48 (m, 1H), 6.86 (m, 1H), 4.87 (m,1H), 3.83 (s, 4H), 2.15-1.67 (m, 14H); MS (m/e) 428 (M+1).

Example 132 3-(2-cyclopentyl-6-pyrrolidin-1-yl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 10.39 (s,1H), 9.51 (s, 1H), 8.59 (s, 1H), 7.29 (m, 1H), 6.86 (m, 1H), 4.85 (m,1H), 3.66 (s, 4H), 2.19-1.68 (m, 12H); MS (m/e) 414 (M+1).

Example 1333-{2-cyclopentyl-6-[(pyridin-3-ylmethyl)amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 1H), 9.45 (s,1H), 8.60 (m, 2H), 7.81 (m, 2H), 7.48 (s, 1H), 7.16 (m, 1H), 6.79 (m,1H), 4.78 (m, 1H), 4.71 (s, 2H), 3.93 (s, 1H), 2.13-1.66 (m, 9H); MS(m/e) 451 (M+1).

Example 134 3-(2-cyclopentyl-6-2-phenethylamino-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 11.59 (s, 1H), 10.39 (s,1H), 9.50 (s, 1H), 8.74 (s, 1H), 7.32-7.29 (m, 6H), 6.86 (m, 1H), 4.83(m, 1H), 3.74 (s, 2H), 2.98 (m, 2H), 2.17-1.67 (m, 9H); MS (m/e) 464(M+1).

Example 1353-{2-Cyclopentyl-6-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 9.52 (s,1H), 8.51 (s, 1H), 7.47 (m, 2H), 7.37 (m, 1H), 7.09 (m, 3H), 6.82 (m,1H), 4.85 (m, 1H), 3.80 (s, 4H), 3.15 (s, 4H), 2.16-1.67 (m, 9H); MS(m/e) 569 (M+1).

Example 1363-[2-cyclopentyl-6-(2-pyrrolidin-1-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H ¹H NMR (400 MHz, DMSO-d₆) δ 10.19 (s, 1H), 9.45(s, 1H), 8.72 (s, 1H), 7.18 (m, 1H), 6.81 (m, 1H), 4.78 (m, 1H), 2.71(m, 3H), 2.46 (m, 6H), 2.20-1.60 (m, 13H); MS (m/e) 457 (M+1).

Example 1373-{2-cyclopentyl-6-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1H), 9.65 (s,1H), 8.32 (m, 1H), 7.61 (m, 1H), 7.25 (m, 1H), 6.95 (m, 1H), 6.86 (m,1H), 6.73 (m, 1H), 4.94 (m, 1H), 4.64 (m, 3H), 4.06 (m, 2H), 3.90 (m,2H), 3.55 (s, 3H), 3.20 (m, 2H), 2.18-1.67 (m, 9H); MS (m/e) 535 (M+1).

Example 1383-[2-cyclopentyl-6-(3-dimethylamino-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.01 (s, 1H), 9.43 (s,1H), 8.65 (s, 1H), 7.09 (m, 1H), 6.79 (m, 1H), 4.75 (m, 1H), 3.69 (m,2H), 3.17 (s, 2H), 2.84 (m, 2H), 2.51 (s, 6H), 2.15-1.62 (m, 10H); MS(m/e) 445 (M+1).

Example 1393-[2-cyclopentyl-6-(3-morpholin-4-yl-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.48 (s,1H), 8.70 (s, 1H), 7.27 (m, 1H), 6.85 (m, 1H), 4.82 (m, 1H), 3.63 (s,4H), 3.32 (s, 4H), 2.46-2.31 (m, 6H), 2.18-1.67 (m, 10H); MS (m/e) 487(M+1).

Example 1405-Chloro-3-{2-cyclopentyl-6-[(2-dimethylamino-ethyl)-methyl-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydro-indol-2-one

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 9.90 (s, 1H), 9.51 (s,1H), 8.28 (s, 1H), 6.83 (m, 1H), 6.69 (m, 1H), 4.81 (m, 1H), 3.81 (s,2H), 3.26 (s, 3H), 2.69 (s, 2H), 2.31-1.69 (m, 15H); MS (m/e) 454 (M+1).

Example 1415-Chloro-3-[2-cyclopentyl-6-(2-diethylamino-ethoxy)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 9.98 (s,1H), 9.48 (s, 1H), 8.27 (s, 1H), 6.87 (m, 1H), 6.70 (m, 1H), 4.83 (m,1H), 3.81 (s, 4H), 2.21-1.65 (m, 14H).

Example 1425-Chloro-3-[2-cyclopentyl-6-(methylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 11.54 (s, 1H), 9.97 (s,1H), 9.48 (s, 1H), 8.44 (s, 1H), 6.86 (m, 1H), 6.70 (m, 1H), 4.80 (m,1H), 3.00 (s, 3H), 2.13-1.68 (m, 9H); MS (m/e) 383 (M+1).

Example 143 5-Chloro-3-(2-cyclopentyl-6-morpholin-4-yl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (s, 1H), 9.49 (s,1H), 8.22 (s, 1H), 6.87 (m, 1H), 6.71 (m, 1H), 4.84 (m, 1H), 3.77 (m,8H), 2.14-1.69 (m, 9H); MS (m/e) 439 (M+1).

Example 1445-Chloro-3-{2-cyclopentyl-6-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydro-indol-2-one

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 9.72 (s, 1H), 9.44 (s,1H), 8.25 (s, 1H), 6.74 (m, 1H), 6.67 (m, 1H), 4.77 (m, 1H), 3.80 (s,4H), 2.56 (s, 6H), 2.36 (s, 8H), 2.18-1.68 (m, 9H); MS (m/e) 509 (M+1).

Compound 145 1-Methyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

A stirred solution of 107 (1 g, 0.0056 mols) in methanol (5 mL) wasstirred overnight at room temperature. The reaction mixture wasconcentrated in vacuo, triturated with ether and collected by filtrationto yield a yellow solid (0.8 g, 95% yield). HPLC (82% purity, retentiontime 2.52 min.-method F), ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (s, 1H),8.07 (d, 1H), 8.04 (s, 1H), 3.80 (s, 3H).

Compound 146 1-Methyl-3-nitro-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one

The nitration to form compound 146 was accomplished following aliterature procedure.³ To a stirred solution of 145 (0.75 g, 0.005 mols)in HNO₃ (1.42 d, 6 mL) and concentrated H₂SO₄ (12 mL) was heated to 100°C. for 2 h. The mixture was cooled to room temperature and poured overice. The resulting precipitate was collected by filtration and dried invacuo to give a yellow solid (0.5 g, 52% yield). m.p. 291-296° C., HPLC(86% purity, retention time 0.872 min.-method F), ¹H NMR (400 MHz,DMSO-d₆) δ 12.69 (s, 1H), 8.25 (d, 1H), 3.1 (s, 3H).

Compound 147 4-Chloro-1-methyl-3-nitro-1H-pyrazolo[3,4-d]pyrimidine

Following the procedure for the preparation of compound 25, compound 146(0.25 g, 1.28 mmol) was treated with phosphorous oxychloride (10 mL) andN,N-dimethylaniline (1 mL). Concentration of the ether afforded 0.270 g(98%) of a red solid which was used without further purification. MS(ES⁺ calculated—213.58; found—214.20 M+H)HPLC (85%) purity, retentiontime 4.700 minutes-(Method D); ¹H NMR (400 MHz, DMSO-d₆) δ 9.09 (s, 1H),4.21 (s, 3H).

Example 1483-(1-Methyl-3-nitro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Utilizing the same procedure for the preparation of Example 29, Example148 was prepared with some modifications. To 5-cyanooxindole (0.192 g,1.21 mmol) in anhydrous THF (10 mL) under nitrogen at −78° C. was addedlithium diisopropylamine (Acros, 1.22 mL of a 2.0M solution inTHF/heptane, 2.43 mmol). The solution was stirred for fifteen minutes atwhich point a solution of compound 147 (0.27 g, 1.29 mmol) in THF (10mL) was added dropwise. After addition was complete the external coolingbath was removed and the reaction was allowed to warm to roomtemperature. After 2 hours the reaction was complete. The reaction wasquenched by the addition of a small amount of a saturated ammoniumchloride solution and concentrated. Dichloromethane (5 mL) and water (5mL) were added and undissolved solid was filtered. The solid was washedwith minimal dichloromethane, as slight product solubility was observed.A red solid (0.285 g, 70%) was obtained and was used without furtherpurification: mp>300 C (dec); MS (ES⁺ calculated—335.28; found—336.16M+H). HPLC (84%) purity; retention time 4.491 minutes-Method D); ¹H NMR(400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 7.32 (s, 1H) 6.99 (d, J=6.24 Hz),4.03 (s, 1H), 4.00 (s, 3H). HPLC Method E:10-100% Acetonitrile over 7minutes. HPLC purity determined at 290 nm.

The following Examples 149-168 in Table 2 were prepared according toprocedures disclosed herein including the general procedure for thepreparation of compounds of Formula XI, disclosed herein, and usingmethods generally known to one skilled in the art.

TABLE 2

Example R² X 149 —CN /—NHCH₂CH═CH₂ 150 —CN /—NHCH(CH₃)₂ 151 —CN/—NH(CH₂)₂NHCOCH₃ 152 H /—Cl 153 —CF₃ /—Cl 154 H /—NHCH₃ 155 H/—NH(CH₂)₂-3-pyridyl 156 H /—NHCH₂-3-pyridyl 157 H/—NH(CH₂)₃—N-morpholine 158 H /—NH(CH₂)₂NHCOCH₃ 159 —CF₃ /—NHCH₃ 160—CF₃ /—NH(CH₂)₂-3-pyridyl 161 —CF₃ /—NHCH₂-3-pyridyl 162 —CF₃/—NH(CH₂)₃—N-morpholine 163 —CF₃ /—NH(CH₂)₂NHCOCH₃ 164 —CN/—O(CH₂)₂-3-pyridyl 165 —CN /—NHCH₂CH(CH₃)₂ 166 —CN /—NHCH₂CH₃ 167 —CN/—N(CH₂CH₂OCH₃)₂ 168 —CN /—N(CH₂CH₂OH)₂

Example 1493-(6-Allylamino-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

A mixture of compound 113 (50 mg, 0.13 mmol), in allylamine (0.99 mL,1.3 mmol) and 2-methoxyethanol (5 mL) were heated to 130° C. for 3 h.The reaction was concentrated, treated with methanol, and filtered. Thesolid was washed with methanol and ethyl ether to give 32 mg (61%) ofthe desired product. Example 149: ¹H NMR (400 MHz, DMSO-d₆) δ 11.6 (bs,1H), 10.4 (s, 1H), 9.5 (s, 1H), 8.7 (s, 1H), 7.3 (d, 1H), 6.8 (d, 1H),6.0 (m, 1H), 5.0-5.3 (m, 2H), 4.8 (m, 2H), 4.2 (s, 2H), 1.6-2.2 (m, 8H);MS (m/e) 400 (M+1); HPLC (99%) purity, retention time 4.212minutes—Method C; mp>300° C.

Example 150 3-(2-cyclopentyl-6-isopropylamino-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Example 150 was made in a similar manner to Example 149 using theappropriate starting materials. Experimental data: ¹HNMR (400 MHz,DMSO-d₆) δ 11.3 (bs, 1H), 10.4 (s, 1H), 9.5 (s, 1H), 8.7 (s, 1H), 7.3(d, 1H), 6.9 (d, 1H), 4.8 (m, 1H), 4.3 (m, 1H), 3.2 (m, 1H), 1.6-2.2 (m,8H), 1.3 (d, 6H); MS (m/e) 402 (M+1); HPLC (98%) purity, retention time4.227 minutes—Method C; mp>300° C.

Example 151 3-(6-(2-acetylamino-ethylamino)-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Example 151 was made in a similar manner to Example 149 using theappropriate starting materials. Experimental data: ¹HNMR (400 MHz,DMSO-d₆) δ 11.7 (bs, 1H), 10.4 (s, 1H), 9.5 (s, 1H), 8.7 (bs, 1H), 8.0(m, 1H), 7.3 (d, 1H), 6.8 (d, 1H), 4.8 (m, 1H), 3.6 (m, 2H), 3.4 (m,3H), 1.6-2.2 (m, 11H); MS (m/e) 445 (M+1); HPLC (99%) purity, retentiontime 3.538 minutes—Method C; mp>300° C.

Example 1523-(6-Chloro-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

To a solution of Oxindole (260 mg, 1.95 mmol) and THF (5 mL) in a 125 mLflask at −78° C. was added 2M LDA in THF/Heptane (1.95 mL, 3.9 mmol).After the reaction was stirred for 30 min, a solution of compound 112(500 mg, 1.95 mmol) in THF (5 mL) was added and the reaction wascontinued for 15 min at −78° C. Next, the reaction was let come to roomtemperature and stirred for an additional 2 h. It was quenched withwater (2 mL) and concentrated. The solid was redissolved in methanol andconcentrated onto silica gel. The silica gel was placed onto a columnsaturated with methylene chloride. The compound was eluted with agradient of methylene chloride to 2% methanol/methylene chloride. Themost pure fractions were concentrated, treated with ethyl ether, andfiltered to give 530 mg (77%) of the desired product. Example 152: ¹HNMR (400 MHz, DMSO-d₆) δ 11.0-11.2 (bs, 1H), 9.0-9.2 (bs, 1H), 7.7-7.9(bs, 1H), 6.8-7.2 (m, 4H), 4.8-5.2 (bs, 1H), 1.6-2.3 (m, 8H); MS (m/e)354 (M+1); HPLC (96%) purity, retention time 5.206 minutes—Method C; mp270-273° C.

Example 153 3-(6-Chloro-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-trifluoromethyl-1,3-dihydro-indol-2-one

To a solution of 5-Trifluoromethyloxindole (390 mg, 1.95 mmol) and THF(5 mL) in a 125 mL flask at −78° C. was added 2M LDA in THF/Heptane(1.95 mL, 3.9 mmol). After the reaction was stirred for 30 min, asolution of compound 112 (500 mg, 1.95 mmol) in THF (5 mL) was added andthe reaction was continued for 15 min at −78° C. Next, the reaction waslet come to room temperature and stirred for an additional 2 h. It wasquenched with water (2 mL) and concentrated. The solid was redissolvedin methanol and concentrated onto silica gel. The silica gel was placedonto a column saturated with methylene chloride. The compound was elutedwith a gradient of methylene chloride to 2% methanol/methylene chloride.The most pure fractions were concentrated, treated with ethyl ether, andfiltered to give 517 mg (63%) of the desired product. Example 153: ¹HNMR(400 MHz, DMSO-d₆) δ 10.7 (bs, 1H), 9.5 (bs, 1H), 8.5 (bs, 1H), 7.3 (d,1H), 7.0 (d, 1H), 4.9-5.0 (m, 1H), 1.6-2.2 (m, 8H); MS (m/e) 422 (M+1);HPLC (98%) purity, retention time 5.979 minutes—Method C; mp>300° C.

Example 154 3-(2-cyclopentyl-6-methylamino-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

A mixture of Compound 152 (40 mg, 0.11 mmol), 2M Methylamine in THF(0.55 mL, 1.1 mmol) and 2-methoxyethanol (2 mL) were heated to 130° C.overnight. The reaction was concentrated, treated with methanol, andfiltered. The solid was washed with methanol and ethyl ether to give 23mg (61%) of the desired product. Example 154: ¹H NMR (400 MHz, DMSO-d₆)δ 13.8 (s, 1H), 10.7 (s, 1H), 8.8 (s, 1H), 7.7 (d, 1H), 7.5 (s, 1H),6.9-7.1 (m, 2H), 5.0 (m, 1H), 3.0 (m, 1H), 2.8 (s, 3H), 1.6-2.2 (m, 8H);MS (m/e) 349 (M+1); HPLC (99%) purity, retention time 3.632minutes—Method C; mp>300° C.

Example 155 3-[2-cyclopentyl-6-(2-pyridin-3-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 155 was prepared in a similar manner to Example 154 as disclosedherein using the appropriate starting materials. Experimental data: ¹HNMR (400 MHz, DMSO-d₆) δ 13.8 (s, 1H), 10.7 (s, 1H), 8.8 (s, 1H),8.4-8.6 (m, 2H), 7.6-7.8 (m, 2H), 7.2-7.5 (m, 1H), 6.9-7.1 (m, 2H), 6.8(d, 1H), 5.0 (m, 1H), 3.8 (m, 1H), 3.6 (m, 2H), 2.8-3.0 (m, 2H), 1.6-2.2(m, 8H); MS (m/e) 440 (M+1); HPLC (90%) purity, retention time 3.376minutes—Method C; mp 258-260° C.

Example 156 3-{2-cyclopentyl-6-[(pyridin-3-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydro-indol-2-one

Example 156 was prepared in a similar manner to Example 154 as disclosedherein using the appropriate starting materials. Experimental data:¹HNMR (400 MHz, DMSO-d₆) δ 13.8 (s, 1H), 10.7 (s, 1H), 8.8 (s, 1H), 8.6(s, 1H), 8.4 (m, 1H), 8.3 (m, 1H), 7.7-7.8 (m, 2H), 7.0 (m, 1H), 6.9 (m,1H), 5.0 (m, 1H), 4.8 (m, 1H), 4.6 (d, 2H), 1.6-2.2 (m, 8H); MS (m/e)426 (M+1); HPLC (97%) purity, retention time 3.476 minutes—Method C; mp216-218° C.

Example 1573-[2-cyclopentyl-6-(3-morpholin-4-yl-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 157 was prepared in a similar manner to Example 154 as disclosedherein using the appropriate starting materials. Experimental data:¹HNMR (400 MHz, DMSO-d₆) δ 13.8 (s, 1H), 10.7 (s, 1H), 8.8 (s, 1H), 7.7(m, 2H), 7.0 (m, 2H), 5.0 (m, 1H), 3.6 (m, 4H), 3.5 (m, 1H), 2.4 (m,6H), 1.6-2.2 (m, 12H); MS (m/e) 462 (M+1); HPLC (99%) purity, retentiontime 3.457 minutes—Method C; mp 242-245° C.

Example 1583-(2-cyclopentyl-6-(2-acetylamino-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Example 158 was prepared in a similar manner to Example 154 as disclosedherein using the appropriate starting materials. Experimental data:¹HNMR (400 MHz, DMSO-d₆) δ 13.8 (s, 1H), 10.7 (s, 1H), 8.8 (s, 1H),7.7-8.0 (m, 3H), 6.8-7.0 (m, 2H), 5.0 (m, 1H), 3.3 (m, 1H), 3.0 (s, 3H),1.6-2.2 (m, 12H); MS (m/e) 420 (M+1); HPLC (95%) purity, retention time3.558 minutes—Method C; mp 238-240° C.

Example 1593(-2-cyclopentyl-6-methylamino-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-trifluoromethyl-1,3-dihydro-indol-2-one

A mixture of Compound 153 (40 mg, 0.095 mmol), 2M Methylamine in THF(0.55 mL, 0.95 mmol) and 2-methoxyethanol (2 mL) were heated to 130° C.overnight. The reaction was concentrated, treated with methanol, andfiltered. The solid was washed with methanol and ethyl ether to give 25mg (63%) of the desired product. Example 159: ¹HNMR (400 MHz, DMSO-d₆) δ11.6 (s, 1H), 10.3 (s, 1H), 9.5 (s, 1H), 8.8 (s, 1H), 7.2 (d, 1H), 6.9(m, 2H), 4.8 (m, 1H), 3.0 (d, 3H), 1.6-2.2 (m, 8H); MS (m/e) 417 (M+1);HPLC (99%) purity, retention time 4.444 minutes—Method C; mp>300° C.

Example 1603-[2-cyclopentyl-6-(2-pyridin-3-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-trifluoromethyl-1,3-dihydro-indol-2-one

Example 160 was prepared in a similar manner to Example 153 as disclosedherein using the appropriate starting materials. Experimental data:¹HNMR (400 MHz, DMSO-d₆) δ 11.4 (s, 1H), 10.3 (s, 1H), 9.5 (s, 1H), 8.7(s, 1H), 8.4-8.6 (m, 3H), 7.7 (m, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 7.0 (m,1H), 4.8 (m, 1H), 3.8 (m, 2H), 2.9 (m, 2H) 1.6-2.2 (m, 8H); MS (m/e) 508(M+1); HPLC (97%) purity, retention time 3.989 minutes—Method C; mp278-280° C.

Example 161 3-{2-cyclopentyl-6-[(pyridin-3-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-5-trifluoromethyl-1,3-dihydro-indol-2-one

Example 161 was prepared in a similar manner to Example 153 as disclosedherein using the appropriate starting materials. Experimental data:¹HNMR (400 MHz, DMSO-d₆) δ 11.7 (s, 1H), 10.3 (s, 1H), 9.5 (s, 1H), 8.7(m, 2H), 8.5 (m, 1H), 7.8 (m, 1H), 7.5 (m, 1H), 7.3 (m, 1H), 7.2 (m,1H), 6.8 (d, 1H), 4.8 (m, 3H), 1.6-2.2 (m, 8H); MS (m/e) 494 (M+1); HPLC(96%) purity, retention time 4.041 minutes—Method C; mp>300° C.

Example 1623-[2-cyclopentyl-6-(3-morpholin-4-yl-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-trifluoromethyl-1,3-dihydro-indol-2-one

Example 162 was prepared in a similar manner to Example 153 as disclosedherein using the appropriate starting materials. Experimental data:¹HNMR (400 MHz, DMSO-d₆) δ 11.4 (s, 1H), 10.3 (s, 1H), 9.5 (s, 1H), 8.8(s, 1H), 7.2 (d, 1H), 7.0 (m, 1H), 6.8 (d, 1H), 4.9 (m, 1H), 3.6 (m,4H), 2.4 (m, 6H), 1.6-2.2 (m, 12H); MS (m/e) 530 (M+1); HPLC (99%)purity, retention time 4.041 minutes—Method C; mp 288-291° C.

Example 163 3-(2-cyclopentyl-6-(2-acetylamino-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-trifluoromethyl-1,3-dihydro-indol-2-one

Example 163 was prepared in a similar manner to Example 153 as disclosedherein using the appropriate starting materials. Experimental data:¹HNMR (400 MHz, DMSO-d₆) δ 11.5 (s, 1H), 10.3 (s, 1H), 9.5 (s, 1H), 8.8(s, 1H), 8.0 (m, 1H), 7.2 (d, 1H), 6.9 (m, 2H), 4.8 (m, 1H), 3.6 (m,2H), 3.4 (m, 2H), 1.6-2.2 (m, 11H); MS (m/e) 488 (M+1); HPLC (99%)purity, retention time 4.314 minutes—Method C; mp>300° C.

Example 164 3-[2-cyclopentyl-6-(2-pyridin-3-yl-ethoxy)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Example 164 was prepared in a similar manner to Example 153 as disclosedherein using the appropriate starting materials. Experimental data: m.p.302-304° C.; MS (ES⁺ calculated: 465.52; found: 466.03 M+H). HPLC (98.5%purity, retention time 9.067 minutes—Method B); ¹HNMR (400 MHz, DMSO-d₆)δ 10.33 (s, 1H), 9.97 (s, 1H), 9.90 (d, 1H), 9.68 (s, 1H), 8.72 (d, 1H),8.53 (s, 1H), 8.27 (t, 1H), 7.25 (d, 1H), 6.88 (d, 1H), 4.98 (m, 1H),4.86 (br s, 1H), 3.84 (t, 2H), 3.34 (m, 1H), 3.15 (t, 2H), 2.20 (m, 2H),2.06 (m, 2H), 1.89 (m, 2H), 1.72 (m, 2H).

Example 165 3-(2-cyclopentyl-6-isobutylamino-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Example 165 was prepared in a similar manner to Example 153 as disclosedherein using the appropriate starting materials. Experimental data: m.p.297-298.5° C.; MS (ES⁺ calculated: 415.50; found: 416.27 M+H). HPLC (99%purity, retention time 11.175 minutes—Method B); ¹HNMR (400 MHz,DMSO-d₆) δ 11.43 (br s, 1H), 10.39 (s, 1H), 9.50 (s, 1H), 8.70 (s, 1H),7.29 (d, 1H), 6.86 (d, 1H), 4.82 (m, 1H), 3.32 (m, 3H), 2.13 (m, 2H),1.97 (m, 3H), 1.82 (m, 2H), 1.68 (m, 2H), 1.00 (d, 6H).

Example 1663-(2-cyclopentyl-6-ethylamino-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Example 166 was prepared in a similar manner to Example 153 as disclosedherein using the appropriate starting materials. Experimental data: m.p.373° C. (dec.); MS (ES⁺ calculated: 387.45; found: 388.22 M+H). HPLC(99% purity, retention time 9.721 minutes—Method B); ¹HNMR (400 MHz,DMSO-d₆) δ 11.59 (s, 1H), 10.37 (s, 1H), 9.48 (s, 1H), 8.74 (s, 1H),7.27 (d, 1H), 6.85 (d, 1H), 4.83 (m, 1H), 3.51 (m, 2H), 3.31 (s, 1H),2.14 (m, 2H), 1.97 (m, 2H), 1.82 (m, 2H), 1.68 (m, 2H), 1.28 (t, 3H).

Example 1673-{6-[bis-(2-methoxyethyl)amino]-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Example 167 was prepared in a similar manner to Example 153 as disclosedherein using the appropriate starting materials. Experimental data: m.p.248.5-249° C.; MS (ES⁺ calculated: 475.55; found: 476.29 M+H). HPLC (99%purity, retention time 11.720 minutes—Method B); ¹HNMR (400 MHz,DMSO-d₆) δ 11.64 (s, 1H), 10.42 (s, 1H), 9.52 (s, 1H), 8.42 (s, 1H),7.29 (d, 1H), 6.87 (d, 1H), 4.87 (m, 1H), 3.93 (s, 4H), 3.65 (m, 4H),3.61 (m, 1H), 3.32 (s, 6H), 2.16 (m, 2H), 1.98 (m, 2H), 1.84 (m, 2H),1.70 (m, 2H).

Example 1683-{6-[bis(2-hydroxyethyl)amino]-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Example 168 was prepared in a similar manner to Example 153 as disclosedherein using the appropriate starting materials. Experimental data: m.p.243-243.5° C.; MS (ES⁺ calculated: 447.50; found: 448.23 M+H). HPLC (95%purity, retention time 9.084 minutes—Method B); ¹HNMR (400 MHz, DMSO-d₆)δ 11.56 (br s, 1H), 10.40 (s, 1H), 9.51 (s, 1H), 8.43 (s, 1H), 7.28 (d,1H), 6.86 (d, 1H), 5.07 (br s, 2H), 4.84 (m, 1H), 3.87 (s, 4H), 3.78 (m,4H), 3.70 (m, 1H), 1.97 (m, 2H), 1.83 (m, 2H), 1.69 (m, 2H).

The following Examples 169-182 in Table 3 were prepared according toprocedures disclosed herein using appropriate starting materials andincluding methods generally known to one skilled in the art.

TABLE 3

Example R² X 169 CN

170 CN

171 CN

172 CN

173 CN

174 CN

175 CN

176 CN

177 CN

178 CN

179 Br

180 Br

181 Br

182 Br Cl

Example 169 3-[2-Cyclopentyl-6-(pyridin-3-ylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1H), 9.66 (s,1H), 9.32 (m, 1H), 9.08 (m, 1H), 8.49 (m, 1H), 7.94-7.80 (m, 2H),7.24-7.22 (m, 1H), 6.88-6.81 (m, 3H), 4.97 (m, 1H), 2.22-1.69 (m, 8H);MS (m/e) 437 (M+1).

Example 1703[2-Cyclopentyl-6-(3-piperidin-1-yl-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (s, 1H), 9.46 (s,1H), 8.73 (s, 1H), 8.03 (s, 1H), 7.22 (s, 1H), 6.82 (m, 1H), 4.81 (m,1H), 3.46 (m, 2H), 3.08 (m, 2H), 2.63 (m, 2H), 2.43 (m, 2H), 2.15-1.38(m, 17H); MS (m/e) 485 (M+1).

Example 1713-{6-[(6-Chloro-pyridin-3-ylmethyl)-amino]-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (s, 1H), 10.32 (s,1H), 9.47 (s, 1H), 8.44 (m, 2H), 7.88 (m, 1H), 7.47 (m, 1H), 7.21 (m,1H), 6.82 (m, 1H), 4.82-4.74 (m, 3H), 2.14-1.66 (m, 9H); MS (m/e) 485(M+1).

Example 1723-[2-Cyclopentyl-6-(methyl-pyridin-3-ylmethyl-amino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 10.42 (s,1H), 9.54 (s, 1H), 8.56 (s, 1H), 8.47 (m, 1H), 8.31 (s, 1H), 7.75 (m,1H), 7.36 (m, 1H), 7.22 (m, 1H), 6.82 (m, 1H), 5.09 (s, 2H), 4.88 (m,1H), 3.28 (s, 3H), 2.17-1.68 (m, 8H); MS (m/e) 465 (M+1).

Example 1733-{2-Cyclopentyl-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 10.40 (s,1H), 9.50 (s, 1H), 8.80 (s, 1H), 8.41 (s, 1H), 8.09 (m, 1H), 7.88 (m,2H), 7.25 (m, 1H), 6.83 (m, 1H), 4.89 (s, 2H), 4.84 (m, 1H), 2.17-1.69(m, 8H); MS (m/e) 519 (M+1).

Example 174 3-[2-Cyclopentyl-6-(2-methoxy-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 11.53 (s, 1H), 10.39 (s,1H), 9.49 (s, 1H), 8.66 (s, 1H), 7.29 (m, 1H), 6.86 (m, 1H), 4.83 (m,1H), 3.65-3.51 (m, 4H), 3.33 (s, 3H), 2.17-1.67 (m, 9H); MS (m/e) 418(M+1).

Example 175 3-[2-Cyclopentyl-6-(3-methoxy-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.14 (s, 1H), 9.44 (s,1H), 8.71 (s, 1H), 7.16 (m, 1H), 6.80 (m, 1H), 4.77 (m, 1H), 3.48 (m,4H), 3.32 (m, 2H), 3.23 (s, 3H), 2.14-1.60 (m, 10H); MS (m/e) 432 (M+1).

Example 1763-{2-Cyclopentyl-6-[(pyridin-4-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (s, 1H), 9.47 (s,1H), 8.55 (m, 2H), 8.48 (m, 2H), 7.40 (m, 2H), 7.19 (m, 1H), 6.79 (m,1H), 4.80 (m, 1H), 4.74 (s, 2H), 3.94 (s, 1H), 2.14-1.66 (m, 8H); MS(m/e) 451 (M+1).

Example 1773-[2-Cyclopentyl-6-(2-morpholin-4-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.48 (s,1H), 8.70 (s, 1H), 7.27 (m, 1H), 6.85 (m, 1H), 4.83 (m, 1H), 3.68 (m,4H), 3.59 (m, 2H), 3.31 (m, 4H), 2.65 (m, 2H), 2.53 (m, 2H), 2.16-1.67(m, 8H); MS (m/e) 473 (M+1).

Example 1783-[2-Cyclopentyl-6-(2-thiomorpholin-4-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.34 (s, 1H), 9.48 (s,1H), 8.70 (m, 1H), 7.27 (m, 1H), 6.85 (m, 1H), 4.83 (m, 1H), 3.57 (m,2H), 2.85-2.55 (m, 12H), 2.16-1.67 (m, 8H); MS (m/e) 489 (M+1).

Example 1795-Bromo-3-{2-cyclopentyl-6-[(pyridin-2-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydro-1H-indol-2-one

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 9.97 (s,1H), 9.49 (s, 1H), 8.57 (m, 1H), 8.44 (m, 1H), 7.79 (m, 1H), 7.50 (m,1H), 7.43 (m, 1H), 7.30 (m, 1H), 6.97 (m, 1H), 6.65 (m, 1H), 4.85 (m,2H), 4.80 (m, 1H), 2.15-1.67 (m, 8H); MS (m/e) 504 (M).

Example 1805-Bromo-3-{2-cyclopentyl-6-[(pyridin-4-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydro-1H-indol-2-one

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (s, 1H), 9.48 (s,1H), 8.49 (m, 2H), 8.28 (s, 1H), 7.39 (m, 3H), 6.91 (m, 1H), 6.62 (m,1H), 4.77 (m, 3H), 2.15-1.66 (m, 9H); MS (m/e) 504 (M).

Example 1815-Bromo-3-[2-cyclopentyl-6-(2-pyridin-3-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-1H-indol-2-one

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 11.37 (s, 1H), 9.98 (s,1H), 9.49 (s, 1H), 8.62-8.42 (m, 3H), 7.72 (m, 2H), 7.33 (m, 1H), 6.99(m, 1H), 6.67 (m, 1H), 4.80 (m, 1H), 3.78 (m, 2H), 3.03 (m, 2H),2.16-1.68 (m, 8H); MS (m/e) 518 (M).

Example 1825-Bromo-3-(6-chloro-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.34 (s,1H), 8.26 (s, 1H), 7.17 (m, 1H), 6.78 (m, 1H), 4.98 (m, 1H), 2.20-1.20(m, 9H); MS (m/e) 433 (M+1).

Example 183 3-(6-Chloro-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

To a stirring solution of 5-cyanooxindole (103 mg, 0.649 mmol) andanhydrous THF (5 mL) in a 15 mL flask at −78° C. was added LDA (649 μL,1.3 mmol). The reaction mixture was stirred for 15 min before adding thecompound 105 (150 mg, 0.649 mmol) as a solid. Following an additional 15min at −78° C., the reaction was allowed to warm to room temperature andstirred for additional 5 h. The reaction mixture was concentrated todryness, taken up into MeOH and concentrated onto silica gel and pumpeddry before subjecting it to flash chromatography on silica gel (gradientelution: 1-10% methanol: dichloromethane) to afford 115 mg (50%) of ayellow solid after trituration in MeOH. Example 183: mp>300° C.; MS (ES⁺calculated: 352.79; found: 353.29 M+H). HPLC (99%) purity, retentiontime 11.253 minutes—Method D); ¹H NMR (400 MHz, DMSO-d₆) δ 10.9 (br s,1H), 9.37 (s, 1H), 8.41 (bs, 1H), 7.46 (d, J=8 Hz, 1H), 6.97 (d, J=8 Hz,1H), 4.30 (t, J=7 Hz, 2H), 1.88 (q, J=3 Hz, 2H), 0.87 (t, J=7 Hz, 3H).

Example 1842-Oxo-3-{2-propyl-6-[(pyridin-3-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2,3-dihydro-1H-indole-5-carbonitrile

Example 183 (25 mg, 0.071 mmol) and 3-(aminomethyl)pyridine (71.8 μL,0.71 mmol) were stirred in 1 mL methoxyethanol overnight at 130° C. inan aluminum block. The reaction mixture was concentrated to dryness andtriturated in 3:1 ether/MeOH. The resulting solid was filtered andpumped dry to afford 23 mg (76%) of a dark yellow solid. Example 184: mp291-295° C.; MS (ES⁺ calculated: 424.47; found: 425.21 M+H). HPLC (99%)purity, retention time 8.438 minutes—Method D); ¹H NMR (400 MHz,DMSO-d₆) δ 11.8 (br s, 1H), 10.39 (s, 1H), 9.43 (s, 1H), 8.64 (s, 1H),8.46 (d, 1H), 7.83 (d, 1H), 7.37 (dd, J=5 Hz, J=3 Hz, 1H), 7.25 (d, J=8Hz, 1H), 4.79 (s 2H), 4.16 (t, J=7 Hz, 2H), 1.83 (m, 2H), 1.09 (t, J=7Hz, 2H), 0.86 (t, J=7 Hz, 3H).

Example 185 2-Oxo-3-[2-propyl-6-(2-pyridin-3-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,3-dihydro-1H-indole-5-carbonitrile

Using the procedure outlined for Example 184, Example 183 (25 mg, 0.071mmol) and 3-(aminoethyl)pyridine (86.7 mg, 0.71 mmol) were stirred in 1mL methoxyethanol overnight at 130° C. in an aluminum block. Thereaction mixture was concentrated to dryness and triturated in a smallamount of MeOH. The resulting solid was filtered and pumped dry toafford 15 mg (48%) of a yellow solid. Example 185: mp 302-305° C.; MS(ES⁺ calculated: 438.50; found: 439.20 M+H). HPLC (99%) purity,retention time 2.996 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ 11.2(br s, 1H), 10.40 (s, 1H), 9.43 (s, 1H), 8.71 (s, 1H), 8.51 (s, 1H),8.42 (d, J=5 Hz, 1H), 7.74 (d, J=8 Hz, 1H), 7.33 (m, 2H), 6.86 (d, J=8Hz, 1H), 4.16 (t, J=7 Hz, 2H), 3.77 (br s, 2H), 3.01 (m2H), 1.84 (m,2H), 0.86 (t, J=7 Hz, 3H).

Example 1862-Oxo-3-{2-propyl-6-[(pyridine-4-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2,3-dihydro-1H-indole-5-carbonitrile

Using the procedure outlined for Example 184, Example 183 (25 mg, 0.071mmol) and 4-(aminomethyl)pyridine (71.8 μL, 0.71 mmol) were stirred in 1mL methoxyethanol overnight at 130° C. in an aluminum block. Thereaction mixture was concentrated to dryness and triturated in a smallamount of MeOH. The resulting solid was filtered and pumped dry toafford 24 mg (79%) of a yellow solid. Example 186: mp 299-302° C.; MS(ES⁺ calculated: 424.47; found: 425.20 M+H). HPLC (92%) purity,retention time 2.90 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ 11.87(br s, 1H), 10.38 (s, 1H), 9.44 (s, 1H), 8.49 (d, J=5 Hz, 2H), 8.33 (brs, 1H), 7.40 (d, J=5 Hz, 1H), 7.23 (d, J=8

Hz, 1H), 6.80 (d, J=8 Hz, 1H), 6.86 (d, J=8 Hz, 1H), 4.16 (t, J=7 Hz,2H), 3.17 (s, J=5 Hz, 2H), 1.84 (m, 2H), 0.87 (t, J=7 Hz, 3H).

Example 1872-Oxo-3-[2-propyl-6-(2-pyridin-2-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2,3-dihydro-1H-indole-5-carbonitrile

Using the procedure outlined for Example 184, Example 183 (25 mg, 0.071mmol) and 2-(aminoethyl)pyridine (84.5 μL, 0.71 mmol) were stirred in 1mL methoxyethanol overnight at 130° C. in an aluminum block. Thereaction mixture was concentrated to dryness and triturated in a smallamount of MeOH. The resulting solid was filtered and pumped dry toafford 23 mg (74%) of a yellow solid. Example 187: mp>300° C.; MS (ES⁺calculated: 438.50; found: 439.22 M+H). HPLC (96%) purity, retentiontime 3.040 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ 11.55 (br s,1H), 10.40 (s, 1H), 9.43 (s, 1H), 8.73 (s, 1H), 8.55 (m, 1H), 7.73 (m,1H) 7.35 (d, J=8, 1H), 7.25 (m, 3H), 6.86 (d, J=8 Hz, 1H), 4.16 (t, J=7Hz, 2H), 3.90 (br s, 2H), 3.16 (m, 2H), 1.84 (m, 2H), 0.86 (t, J=7 Hz,3H).

Example 1885-Bromo-3-(6-chloro-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

To a stirring solution of 5-bromooxindole (229 mg, 1.08 mmol) andanhydrous THF (10 mL) in a 25 mL flask at −78° C. was added LDA (1.08mL, 2.16 mmol). The reaction mixture was stirred for 15 min beforeadding the substrate 105 (250 mg, 1.08 mmol) as a solid. Following anadditional 15 min at −78° C., the reaction was allowed to warm to roomtemperature and stirred overnight (reaction may have been complete after2 h). The reaction mixture was concentrated to dryness, taken up intoMeOH and concentrated onto silica gel and pumped dry before subjectingit to flash chromatography on silica gel (gradient elution: 1-2-3%methanol: dichloromethane) to afford 210 mg (48%) of a yellow solid thatprecipitated in the reaction tubes and was triturated in MeOH. Example188: mp >300° C.; MS (ES⁺ calculated: 406.67; found: 407.87 M+H). HPLC(99%) purity, retention time 12.31 minutes—Method D); ¹H NMR (400 MHz,DMSO-d₆) δ 10.5 (br s, 1H), 9.31 (s, 1H), 8.26 (br s, 1H), 7.17 (d, J=8Hz, 1H), 6.79 (d, J=8 Hz, 1H), 4.28 (br s, 2H), 1.86 (q, J=3 Hz, 2H),0.87 (t, J=8 Hz, 3H).

Example 1895-Bromo-3-[2-propyl-6-(2-pyridin-3-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 184, Example 188 (25 mg, 0.0614mmol) and 3-(aminoethyl)pyridine (75 mg, 0.614 mmol) were stirred in 1mL methoxyethanol overnight at 130° C. in an aluminum block. Thereaction mixture was concentrated to dryness and triturated in a smallamount of MeOH. The resulting solid was filtered and pumped dry toafford 15 mg (50%) of a yellow solid. Example 189: mp 294-297° C.; MS(ES⁺ calculated: 492.38; found: 492.50 M+H). HPLC (80%) purity,retention time 3.437 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ 11.3(br s, 1H), 10.01 (s, 1H), 9.42 (s, 1H), 8.52 (m, 2H), 8.43 (s, 1H),7.73 (m, 1H), 7.65 (m, 1H), 7.32 (m, 2H), 6.98 (m, 1H), 6.67 (d, J=8 Hz)4.14 (t, J=7 Hz, 2H), 3.78 (br s, 2H), 3.38 (m), 3.03 (m 2H), 1.84 (m,2H), 0.86 (m, 3H).

Example 1905-Bromo-3-{2-propyl-6-[(pyridine-4-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 184, Example 188 (25 mg, 0.0614mmol) and 4-(aminomethyl)pyridine (62 μL, 0.614 mmol) were stirred in 1mL methoxyethanol overnight at 130° C. in an aluminum block. Thereaction mixture was concentrated to dryness and triturated in a smallamount of MeOH. The resulting solid was filtered and pumped dry toafford 4 mg (14%) of a yellow solid. Example 190: mp>300° C.; MS (ES⁺calculated: 478.36; found: 478.61 M+H). HPLC (74%) purity, retentiontime 3.461 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ 11.69 (br s,1H), 9.4 (s, 1H), 8.50 (d, J=6 Hz), 8.24 (s, 1H), 7.42 (d, J=7 Hz, 1H),6.93 (d, J=8 Hz, 1H), 4.79 (d, J=6 Hz, 1H), 4.14 (m, 2H), 1.84 (m, 2H),0.87 (t, J=7 Hz, 3H).

Example 1915-Bromo-3-[2-propyl-6-(2-pyridin-2-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 184, Example 188 (25 mg, 0.0614mmol) and 2-(aminoethyl)pyridine (73 μL, 0.614 mmol) were stirred in 1mL methoxyethanol overnight at 130° C. in an aluminum block. Thereaction mixture was concentrated to dryness and triturated in a smallamount of MeOH. The resulting solid was filtered and pumped dry toafford 14 mg (46%) of a yellow solid. Example 191: mp 283-291° C.; MS(ES⁺ calculated: 492.38; found: 492.41 M+H). HPLC (86%) purity,retention time 3.60 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ 11.32(br s, 1H), 10.02 (s, 1H), 9.42 (s, 1H), 8.55 (d, 2H), 7.75 (m, 1H) 7.37(d, J=8, 1H), 7.26 (m, 3H), 7.00 (d, 1H), 6.67 (d, J=8 Hz, 1H), 4.13 (t,J=7 Hz, 2H), 3.91 (br s, 2H), 3.19 (m, 2H), 1.83 (m, 2H), 0.86 (m, 3H).

Example 1925-Bromo-3-[2-propyl-6-(3,3,3-trifluoro-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 188 (25 mg, 0.0614 mmol) and 3,3,3-trifluoro-n-propylaminehydrochloride. (89 mg, 0.614 mmol) were stirred in 1 mL methoxyethanolbefore adding NaH (19.6 mg, 0.491 mmol) and heated overnight at 130° C.in an aluminum block. The reaction mixture was concentrated to drynessand triturated in a small amount of MeOH. The resulting solid wasfiltered and pumped dry to afford 24 mg (81%) of a yellow solid. Example192: mp>300° C.; MS (ES⁺ calculated: 483.29; found: 483.61 M+H). HPLC(99%) purity, retention time 4.915 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 11.53 (br s, 1H), 10.86 (s, 1H), 10.02 (s, 1H), 9.43 (s, 1H),8.45 (s, 1H), 7.01 (d, 2H) 6.67 (d, 1H), 4.14 (t, J=7 Hz, 2H), 3.76 (brs, 2H), 2.70 (m, 2H), 1.83 (m, 2H), 0.86 (m, 3H).

Example 1933-(6-Allylamino-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-bromo-1,3-dihydro-indol-2-one

Example 188 (34 mg, 0.0835 mmol) and allylamine (62.7 μL, 0.835 mmol)were heated in 1 mL EtOH at 130° C. in microwave for 10 min. Uponcooling, the product precipitated in the reaction tube. The resultingsolid was filtered and pumped dry to afford 30 mg (84%) of a brightyellow solid. Example 193: mp 322-326° C.; MS (ES⁺ calculated: 427.31;found: 428.3 M+H). HPLC (100%) purity, retention time 4.223minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ 11.37 (s, 1H), 9.98 (s,1H), 9.41 (s, 1H), 8.52 (s, 1H), 7.11 (br s, 1H), 7.01 (d, 1H), 6.66 (d,J=8 Hz, 1H), 6.03 (m, 1H), 5.30 (d, 1H), 5.15 (d, 1H) 4.13 (s, 4H), 1.83(m, 2H), 0.86 (m, 3H).

Example 1945-Bromo-3-[6-((S)-2-hydroxy-propylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 184, Example 188 (30 mg, 0.0737mmol) and (S)-(+)-1-amino-2-propanol (58 μL, 0.737 mmol) were heated in1 mL EtOH at 130° C. in microwave for 10 min. Upon cooling, the productprecipitated in the reaction tube. The resulting solid was filtered andpumped dry to afford 32 mg (97%) of a bright yellow solid. Example 194:mp 322-326° C.; MS (ES⁺ calculated: 445.32; found: 445.65 M+H). HPLC(97%) purity, retention time 3.735 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 11.12 (br s, 1H), 9.99 (s, 1H), 9.41 (s, 1H), 8.52 (s, 1H),7.00 (d, 1H), 6.68 (d, J=8 Hz, 1H), 4.97 (br s, 1H), 4.13 (t, J=7 Hz,2H), 3.94 (br s, 1H), 3.65 (br s, 1H) 3.23 (m, 1H), 1.83 (m, 2H), 1.22(d, J=6 Hz, 2H), 1.10 (d, J=6 Hz, 1H), 0.86 (m, 3H).

Example 1955-Bromo-3-[6-((R)-2-hydroxy-propylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 184, Example 188 (30 mg, 0.0737mmol) and (R)-(−)-1-amino-2-propanol (58 μL, 0.737 mmol) were heated in1 mL EtOH at 130° C. in microwave for 10 min. Upon cooling, the productprecipitated in the reaction tube. The resulting solid was filtered andpumped dry to afford 27 mg (82%) of a yellow solid. Example 195: mp 310°C. (dec); MS (ES⁺ calculated: 445.32; found: 445.66 M+H). HPLC (95%)purity, retention time 3.741 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 11.12 (br s, 1H), 9.99 (s, 1H), 9.41 (s, 1H), 8.52 (s, 1H),7.00 (d, 1H), 6.68 (d, J=8 Hz, 1H), 4.97 (br s, 1H), 4.13 (t, J=7 Hz,2H), 3.94 (br s, 1H), 3.65 (br s, 1H) 3.23 (m, 1H), 1.83 (m, 2H), 1.22(d, J=6 Hz, 2H), 1.10 (d, J=6 Hz, 1H), 0.86 (m, 3H).

Example 1965-Bromo-3-{2-propyl-6-[(pyridin-3-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 184, Example 188 (30 mg, 0.0737mmol) and 3-(aminoethyl)pyridine (74.6 μL, 0.737 mmol) were stirred in 1mL EtOH at 130° C. in microwave for 10 min. Upon cooling, the productprecipitated in the reaction tube. The resulting solid was filtered andpumped dry to afford 15 mg (43%) of a yellow solid. Example 196: mp277-281° C.; MS (ES⁺ calculated: 478.36; found: 478.54 M+H). HPLC (92%)purity, retention time 3.490 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 9.98 (s, 1H), 9.42 (s, 1H), 8.66 (s, 1H), 8.45 (s, 1H), 8.40(m, 1H), 7.83 (d, 1H), 7.48 (br s, 1H), 7.35 (m, 1H), 6.66 (d, 1H) 4.78(d, 2H), 4.14 (t, J=7 Hz, 2H), 1.84 (m, 2H), 0.86 (m, 3H).

Example 1975-Bromo-3-[6-(2-dimethylamino-ethylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 184, Example 188 (30 mg, 0.0737mmol) and N,N-dimethylaminoethylamine (65 μL, 0.737 mmol) were heated in1 mL EtOH at 130° C. in microwave for 10 min. Upon cooling, the productprecipitated in the reaction tube. The resulting solid was filtered andpumped dry to afford 16 mg (47%) of a yellow solid. Example 197: mp270-274° C.; MS (ES⁺ calculated: 458.36; found: 458.69 M+H). HPLC (96%)purity, retention time 3.534 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 9.97 (s, 1H), 9.41 (s, 1H), 8.51 (s, 1H), 6.99 (d, J=8 Hz,1H), 6.85 (br s, 1H), 6.66 (d, J=8 Hz, 1H), 4.13 (t, J=7 Hz, 2H), 3.58(br d, 1H), 2.61 (m, 2H) 2.28 (s, 6H), 1.83 (m, 2H), 0.86 (m, 3H).

Example 1985-Bromo-3-[6-(3-dimethylamino-propylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 184, Example 188 (30 mg, 0.0737mmol) and N,N-dimethylaminopropylamine (93 μL, 0.737 mmol) were heatedin 1 mL EtOH at 130° C. in microwave for 10 min. Upon cooling, theproduct precipitated in the reaction tube. The resulting solid wasfiltered and pumped dry to afford 25 mg (79%) of a yellow solid. Example198: mp 286-290° C.; MS (ES⁺ calculated: 472.39; found: 472.62 M+H).HPLC (98%) purity, retention time 3.464 minutes—Method C); ¹H NMR (400MHz, DMSO-d₆) δ 9.92 (s, 1H), 9.41 (s, 1H), 8.54 (s, 1H), 7.10 (br s,1H), 6.97 (d, J=8 Hz, 1H), 6.65 (d, J=8 Hz, 1H), 4.13 (t, J=7 Hz, 2H),3.49 (br d, 1H), 2.24 (s, 6H), 1.83 (m, 4H), 0.86 (m, 3H).

Example 199 3-[6-(3-Amino-propylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-bromo-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 184, Example 188 (40 mg, 0.0983mmol) and 1,3-propanediamine (83 μL, 0.983 mmol) were heated in 1 mLEtOH at 130° C. in microwave for 10 min. Upon cooling, the productprecipitated in the reaction tube. The resulting solid was filtered andpumped dry to afford 33 mg (76%) of a yellow solid. Example 199: mp>300°C.; MS (ES⁺ calculated: 444.34; found: 444.61 M+H). HPLC (94%) purity,retention time 3.297 minutes—Method C); ¹H NMR (400 MHz, DMSO-d₆) δ 9.50(s, 1H), 9.37 (s, 1H), 8.57 (s, 1H), 7.75 (br s), 6.77 (d, J=8 Hz, 1H),6.57 (d, J=8 Hz, 1H), 6.35 (br s, 1H) 4.07 (t, J=7 Hz, 2H), 3.50 (s,2H), 2.84 (m, 1H), 1.83 (m, 4H), 0.86 (m, 3H).

Example 200 3-[6-(2-Amino-ethylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-bromo-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 184, Example 188 (40 mg, 0.0983mmol) and 1,3-ethanediamine (65.7 μL, 0.983 mmol) were heated in 1 mLEtOH at 130° C. in microwave for 10 min. Upon cooling, the productprecipitated in the reaction tube. The resulting solid was filtered andpumped dry to afford 28 mg (66%) of a yellow solid. Example 200: mp272-276° C.; MS (ES⁺ calculated: 430.31; found: 430.70 M+H). HPLC (87%)purity, retention time 3.383 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 9.56 (s, 1H), 9.38 (s, 1H), 8.55 (s, 1H), 7.45 (br s), 6.80(d, J=8 Hz, 1H), 6.58 (d, J=8 Hz, 1H), 6.47 (br s, 1H) 4.09 (m, 2H),3.50 (s, 2H), 3.03 (s, 2H), 1.83 (m, 4H), 0.86 (m, 3H).

Example 2015-Bromo-3-[6-(3-methylamino-propylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one hydrochloride

Using the procedure outlined for Example 184, Example 188 (50 mg, 0.123mmol) and N-(3-aminopropyl)-N-methyl carbamic acid t-butyl ester (231mg, 1.23 mmol) were heated in 1 mL EtOH at 130° C. in microwave for 10min. Upon cooling, the product precipitated in the reaction tube. Theresulting solid was filtered and pumped dry before stirring in 5 mL of4N HCl/dioxane for 1 h at RT. The reaction mixture was pumped dry,triturated in ether and filtered to afford 39 mg (64%) of a yellowsolid. Example 201: mp 271-273° C.; MS (ES⁺ calculated: 458.61; found:459.4 M+H). HPLC (94%) purity, retention time 3.406 minutes—Method C);¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (s, 1H), 7.07 (s, 1H), 6.76 (s, 1H),4.07 (s, 1H), 3.50 (s, 2H), 3.02 (s, 1H), 2.55 (m, 3H), 2.02 (s, 2H),1.84 (m, 2H), 0.86 (m, 3H).

Example 2025-Bromo-3-[6-(2-morpholin-4-yl-ethylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 184, Example 188 (30 mg, 0.0737mmol) and N-(2-aminoethyl) morpholine (96.7 μL, 0.737 mmol) were heatedin 1 mL EtOH at 130° C. in microwave for 10 min. Upon cooling, theproduct precipitated in the reaction tube. The resulting solid wasfiltered and pumped dry to afford 30 mg (81%) of a yellow solid. Example202: mp 299-303° C.; MS (ES⁺ calculated: 500.40; found: 500.60 M+H).HPLC (95%) purity, retention time 3.739 minutes—Method C); ¹H NMR (400MHz, DMSO-d₆) δ 9.97 (s, 1H), 9.41 (s, 1H), 8.51 (br s, 1H), 7.00 (d,1H), 6.87 (m, 1H), 6.66 (d, J=8 Hz, 1H), 4.13 (t, J=7 Hz, 2H), 3.64 (m,8H), 2.65 (t, 2H), 1.83 (m, 4H), 0.86 (m, 3H).

Example 2035-Bromo-3-[6-(3-morpholin-4-yl-propylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 184, Example 188 (30 mg, 0.0737mmol) and N-(3-aminopropyl) morpholine (107 μL, 0.737 mmol) were heatedin 1 mL EtOH at 130° C. in microwave for 10 min. Upon cooling, theproduct precipitated in the reaction tube. The resulting solid wasfiltered and pumped dry to afford 30 mg (95%) of a yellow solid. Example203: mp 298-303° C.; MS (ES⁺ calculated: 514.43; found: 514.51 M+H).HPLC (98%) purity, retention time 3.569 minutes—Method C); ¹H NMR (400MHz, DMSO-d₆) δ 9.56 (s, 1H), 9.38 (s, 1H), 8.55 (s, 1H), 7.45 (br s),6.80 (d, J=8 Hz, 1H), 6.58 (d, J=8 Hz, 1H), 6.47 (br s, 1H) 4.09 (m,2H), 3.50 (s, 2H), 3.03 (s, 2H), 2.37 (m, 2H), 1.83 (m, 4H), 0.86 (m,3H).

Example 204 3-(6-Chloro-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic aciddimethylamide

To a stirring solution of 5-dimethylsulfonamideoxindole (208 mg, 0.866mmol) and anhydrous THF (7.5 mL) in a 15 mL flask at −78° C. was addedLDA (0.866 mL, 1.732 mmol). The reaction mixture was stirred for 15 minbefore adding the substrate 105 (200 mg, 0.866 mmol) as a solid.Following an additional 15 min at −78° C., the reaction was allowed towarm to room temperature and stirred over weekend (reaction may havebeen complete after 2 h). The reaction mixture was concentrated todryness, taken up into MeOH and concentrated onto silica gel and pumpeddry before subjecting it to flash chromatography on silica gel (gradientelution: 1-5% methanol: dichloromethane) to afford 196 mg (52%) of ayellow solid that precipitated in the reaction tubes and was trituratedin ether. Example 204: mp>300° C.; MS (ES⁺ calculated: 434.91; found:435.42 M+H). HPLC (83%) purity, retention time 4.24 minutes—Method C);¹H NMR (400 MHz, DMSO-d6) δ 10.73 (br s, 1H), 9.35 (br s, 1H), 8.62 (brs, 1H), 7.40 (d, J=8 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 4.26 (t, J=3 Hz,2H), 2.62 (s, 6H) 1.86 (q, J=3 Hz, 2H), 0.87 (t, J=8 Hz, 3H).

Example 205 3-[6-(2-Dimethylamino-ethylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic aciddimethylamide

Using the procedure outlined for Example 184, Example 188 (50 mg, 0.115mmol) and N,N-dimethylaminoethylamine (101 mg, 1.15 mmol) were heated in1 mL EtOH at 130° C. in microwave for 10 min. Upon cooling, the productprecipitated in the reaction tube. The resulting solid was filtered andpumped dry to afford 39 mg (70%) of a yellow solid. Example 205: mp259-263° C.; MS (ES⁺ calculated: 486.60; found: 487.30 M+H). HPLC (96%)purity, retention time 2.972 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 10.15 (br s, 1H), 9.39 (s, 1H), 8.83 (s, 1H), 7.20 (d, J=8Hz, 1H), 6.86 (d, J=8 Hz, 1H), 4.12 (t, J=7 Hz, 2H), 3.58 (br s, 2H),2.77 (t, 1H) 2.57 (s, 9H), 2.22 (s, 6H), 2.16 (s, 2H), 1.83 (m, 2H),0.86 (m, 3H).

Scheme 4 discloses a general procedure for the preparation of compoundsof the invention wherein R⁶ is an alkoxyalkyl group and R² is chloro.

Compound 206 and 2075-Amino-1-(2-ethoxyethyl)-1H-pyrazole-4-carbonitrile3-Amino-1-(2-ethyoxyethyl)-1H-pyrazole-4-carbonitrile

3-Amino-4-cyanopyrazole 1 (3.24 g, 30.0 mmol), 2-bromoethoxyethylether(6.12 g, 40.0 mmol), and potassium carbonate (5.53 g, 40.0 mmol) werecombined in 20 mL anhydrous N,N-dimethylformamide and heated under argonat 80° C. overnight. Solids were removed by filtration and the motherliquor was concentrated to afford after chromatography on silica(gradient elution 2:1 to 0:1 petroleum ether:ethyl acetate) twoproducts: KA—a higher RF white solid (2.08 g, 39%) and KB—a lower RFpale yellow solid (2.21 g, 41%). Compound 206: mp 130-132° C.; MS (ES⁺calculated: 180.21; found: 181.16 M+H). HPLC (92% purity, retention time6.533 minutes—Method A); ¹H NMR (400 MHz, DMSO-d⁶): δ 7.53 (s, 1H), 6.48(s, 2H), 4.03 (t, J=6 Hz, 2H), 3.62 (t, J=6 Hz, 2H), 3.42 (q, J=7 Hz,2H), 1.06 (t, J=7 Hz, 3H). Compound 207: mp 65-67° C.; MS (ES⁺calculated: 180.21; found: 181.16 M+H). HPLC (100% purity, retentiontime 5.277 minutes—Method A); ¹H NMR (400 MHz, DMSO-d⁶): δ 8.04 (s, 1H),5.51 (s, 2H), 4.00 (t, J=6 Hz, 2H), 3.64 (t, J=6 Hz, 2H), 3.41 (q, J=7Hz, 2H), 1.06 (t, J=7 Hz, 3H).

Compound 208 3-Amino-1-(2-ethoxyethyl)-1H-pyrazole-4-carboxylic acidamide

Compound 207 (2.39 g, 13.3 mmol) was added in one portion to 3 mLconcentrated sulfuric acid. The mixture was stirred for two hours atwhich point the mixture had become homogeneous. The sulfuric acidsolution was added dropwise (violent) to 30 mL cold concentratedammonium hydroxide solution. The mixture was stirred under an air streamto dryness over 72 hours. Several milliliters of water were added and alight brown solid was collected by filtration. The solid was dried invacuo to afford 1.977 g (75%). Compound 208: MS (ES⁺ calculated: 198.23;found: 199.80 M+H). HPLC (73% purity, retention time 2.944minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 7.87 (s, 1H), 7.20 (brs, 1H), 6.67 (br s, 1H), 5.33 (s, 2H), 3.96 (t, J=5 Hz, 2H), 3.64 (t,J=5 Hz, 2H), 3.39 (q, J=7 Hz, 2H), 1.07 (t, J=7 Hz, 3H).

Compound 2092-(2-Ethoxyethyl)-2,7-dihydropyrazolo[3,4-d]pyrimidine-4,6-dione

Compound 208 (1.85 g, 0.93 mmol) and urea (5.55 g, 92.5 mmol) were mixedand heated at 200° C. to form a melt for two hours. The solution waspermitted to cool to room temperature and 10 mL water was added. Themixture was refluxed for one hour, was permitted to cool, and theproduct was collected by filtration to afford a tan solid (0.995 g,47%). Compound 209: mp>300° C.; MS (ES⁺ calculated: 224.22; found:224.21 M+). HPLC (75% purity, retention time 3.785 minutes—Method A); ¹HNMR (400 MHz, DMSO-d⁶): δ 9.60 (br s, 2H), 8.27 (s, 1H), 4.23 (t, J=6Hz, 2H), 3.72 (t, J=6 Hz, 2H), 3.43 (q, J=7 Hz, 2H), 1.05 (t, J=7 Hz,3H).

Compound 210 4,6-Dichloro-2-(2-ethoxyethyl)-2H-pyrazolo[3,4-d]pyrimidine

Compound 209 (1 g, 4.5 mmol) was suspended in 50 mL phosphorusoxychloride and was refluxed under argon overnight. The now homogeneoussolution was concentrated in vacuo. Ice was added and the mixture wasbasified by the addition of 10N sodium hydroxide solution. The organicswere extracted into ether. The ether was dried (magnesium sulfate) andwas concentrated to afford 0.982 g (84%) of a white solid. Compound 210:MS (ES⁺ calculated: 261.11; found: 261.57 M+). HPLC (95% purity,retention time 11.686 minutes—Method A); ¹H NMR (400 MHz, DMSO-d⁶): δ9.02 (s, 1H), 4.65 (t, J=5 Hz, 2H), 3.90 (t, J=5 Hz, 2H), 3.43 (q, J=7Hz, 2H), 1.03 (t, J=7 Hz, 3H).

Example 2115-Chloro-3-[6-chloro-2-(2-ethoxy-ethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

To 5-chlorooxindole (168 mg, 1.0 mmol) in 5 mL anhydrous tetrahydrofuranunder argon at −78° C. was added lithium diisopropylamide (1.05 mL of a2.0M solution in THF/hexane, 2.1 mmol) dropwise. The solution wasstirred fifteen minutes at which point Compound 210 (261 mg, 1.0 mmol)was added in one portion. The solution was permitted to warm to roomtemperature and was stirred for two hours. The solution was thenconcentrated and subjected to chromatography on silica (gradient elution1 to 3% methanol:dichloromethane). Fractions containing the desiredproduct were further purified by trituration with methanol to affordfollowing filtration 290 mg (74%) of a yellow solid. Example 211:mp>300° C.; MS (ES⁺ calculated: 392.25; found: 392.61 M+). HPLC (100%purity, retention time 11.993 minutes—Method B); ¹H NMR (400 MHz,DMSO-d⁶): δ 10.44 (br s, 1H), 9.30 (br s, 1H), 8.07 (br s, 1H), 7.04 (m,1H), 6.80 (m, 1H), 4.46 (m, 2H), 3.80 (m, 2H), 3.47 (m, 2H), 1.08 (t,J=7 Hz, 3H).

Example 2125-Chloro-3-[2-(2-ethoxy-ethyl)-6-(2-pyridin-3-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 211 (30 mg, 0.076 mmol) and 3-(2′-aminoethyl)pyridine (93 mg,0.76 mmol) were combined in 2 mL ethanol and subjected to reaction in amicrowave at 200° C. for ten minutes. On cooling, a brown yellow solidformed which was isolated by filtration. The solid was dried in vacuoaffording 6 mg (17%). Example 212: mp 224-6° C.; MS (ES⁺ calculated:477.96; found: 478.49 M+H). HPLC (86% purity, retention time 7.996minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 10.82 (s, 1H), 10.00 (brs, 1H), 9.47 (s, 1H), 8.60-8.80 (m, 3H), 7.74 (m, 1H), 7.32 (m, 1H),6.90-6.60 (m, 2H), 4.32 (m, 2H), 3.80 (m, 2H), 3.44 (m, 4H), 3.00 (m,2H), 1.05 (m, 3H).

Example 2135-Chloro-3-{2-(2-ethoxy-ethyl)-6[(pyridin-3-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydro-indol-2-one

Example 211 (30 mg, 0.076 mmol) and 3-aminomethylpyridine (82 mg, 0.76mmol) were combined in 2 mL ethanol and subjected to reaction in amicrowave at 130° C. for ten minutes. On cooling a yellow solid formedwhich was isolated by filtration. The solid was dried in vacuo affording22 mg (62%). Example 213: mp 294-6° C.; MS (ES⁺ calculated: 463.93;found: 464.44 M+H). HPLC (92% purity, retention time 8.063minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 10.87 (s, 1H), 9.97 (s,1H), 9.44 (s, 1H), 8.65-8.48 (m, 2H), 7.80-7.35 (m, 3H), 6.83 (m, 1H),6.64 (m, 1H), 4.85-4.30 (m, 4H), 3.74 (m, 2H), 3.44 (m, 3H), 1.07 (m,3H).

Example 2145-Chloro-3-{2-(2-ethoxy-ethyl)-6-[(pyridine-4-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydro-indol-2-one

Example 211 was reacted with 4-aminomethylpyridine to afford a yellowsolid. Yield: 45%. Example 214: mp 298-9° C.; MS (ES⁺ calculated:463.93; found: 464.46 M+H). HPLC (81% purity, retention time 7.855minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 10.90 (s, 1H), 10.00 (s,1H), 9.45 (s, 1H), 8.50 (m, 2H), 8.10 (s, 1H), 7.38 (m, 2H), 6.81 (m,1H), 6.65 (m, 1H), 4.80-4.24 (m, 4H), 3.76 (m, 2H), 3.48 (m, 2H), 1.08(m, 3H).

Example 2155-Chloro-3-[2-(2-ethoxy-ethyl)-6-(3-methylamino-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 211 was reacted with N-(3-aminopropyl)-N-methylcarbamicacid-t-butyl ester. The product obtained by filtration from theethanolic solution was taken up into 4 mL 4N hydrochloric acid:dioxaneand stirred at room temperature for one hour. The reaction wasconcentrated and the solid was triturated with ethyl ether to affordafter filtering 28 mg (77%) of a yellow solid—isolated as thehydrochloride salt. Example 215: mp 275-7° C.; MS (ES⁺ calculated:443.94; found: 444.46 M+H). HPLC (100% purity, retention time 7.847minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 10.15 (br s, 1H), 9.40(br s, 1H), 9.83 (m, 2H), 8.34 (br s, 1H), 7.66 (br s, 1H), 7.00 (m,1H), 6.84 (m, 1H), 4.45 (m, 4H), 3.80 (m, 2H), 3.60-3.45 (m, 5H), 3.04(m, 2H), 2.56 (m, 2H), 2.02 (m, 2H), 1.08 (m, 3H).

Example 2165-Chloro-3-[6-(2-dimethylamino-ethylamino)-2-(2-ethoxy-ethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 211 was reacted with N,N-dimethylethylenediamine to afford ayellow solid. Yield:59%. Example 216: mp 293-5° C.; MS (ES⁺ calculated:443.94; found: 444.49 M+H). HPLC (96% purity, retention time 8.086minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 9.97 (s, 1H), 9.43 (s,1H), 8.34 (br s, 1H), 6.88 (m, 2H), 6.69 (d, J=8 Hz, 1H), 4.30 (m, 2H),3.76 (m, 2H), 3.67 (m, 2H), 3.40 (m, 2H), 3.27 (m, 2H), 2.64 (m, 2H),2.30 (s, 6H), 1.07 (m, 3H).

Example 2175-Chloro-3-[2-(2-ethoxy-ethyl)-6-(2-morpholin-4-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 211 was reacted with N-aminoethylmorpholine to afford a yellowsolid. Yield: 62%. Example 217: mp 293-4° C.; MS (ES⁺ calculated:485.98; found: 486.45 M+H). HPLC (100% purity, retention time 8.513minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 10.84 (s, 1H), 10.00 (s,1H), 9.47 (s, 1H), 8.38 (br s, 1H), 6.88 (m, 2H), 6.69 (m, 1H), 4.32 (m,2H), 3.78 (m, 2H), 3.63 (m, 8H), 3.43 (m, 2H), 2.63 (m, 2H), 2.37 (m,2H), 1.07 (m, 3H).

Example 2185-Chloro-3-[2-(2-ethoxy-ethyl)-6-((R)-2-hydroxy-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 211 was reacted with (R)-2-hydroxy-1-aminopropane to afford ayellow solid. Yield:95%. Example 218: mp>300° C.; MS (ES⁺ calculated:430.90; found: 431.46 M+H). HPLC (99% purity, retention time 11.949minutes—Method A); ¹H NMR (400 MHz, DMSO-d⁶): δ 11.08 (br s, 1H), 9.95(s, 1H), 9.42 (s, 1H), 8.32 (s, 1H), 6.85 (m, 1H), 6.68 (m, 1H), 4.96(br s, 1H), 4.30 (m, 2H), 3.78 (m, 2H), 3.67 (br s, 1H), 3.49 (m, 2H),1.20 (d, J=6 Hz, 3H), 1.07 (m, 3H).

Example 2195-Chloro-3-[2-(2-ethoxy-ethyl)-6-((S)-2-hydroxy-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 211 was reacted with (S)-2-hydroxy-1-aminopropane to afford ayellow solid. Yield:89%. Example 219: mp>300° C.; MS (ES⁺ calculated:430.90; found: 431.43 M+H). HPLC (99% purity, retention time 11.924minutes—Method A); ¹H NMR (400 MHz, DMSO-d⁶): δ 11.10 (br s, 1H), 9.95(s, 1H), 9.43 (s, 1H), 8.32 (s, 1H), 6.82 (m, 1H), 6.66 (m, 1H), 4.96(br s, 1H), 4.30 (m, 2H), 3.78 (m, 2H), 3.67 (br s, 1H), 3.43 (m, 2H),1.20 (d, J=6 Hz, 3H), 1.07 (m, 3H).

Scheme 5 discloses a general procedure for the preparation of compoundsof the invention wherein R⁶ is an alkoxyalkyl group and R² is bromo.

Compound 220 and 2215-Amino-1-(2-methoxyethyl)-1H-pyrazole-4-carbonitrile3-Amino-1-(2-methoxyethyl)-1H-pyrazole-4-carbonitrile

3-Amino-4-cyanopyrazole (1) was reacted with bromomethylmethyl ether toafford LA (43%) and LB (49%) as white solids. Compound 220: mp 120-122°C.; MS (ES⁺ calculated: 166.18; found: 167.26 M+H). HPLC (90% purity,retention time 4.716 minutes—Method A); ¹H NMR (400 MHz, DMSO-d⁶): δ7.52 (s, 1H), 6.49 (br s, 2H), 4.04 (t, J=5 Hz, 2H), 3.59 (t, J=5 Hz,2H), 3.29 (s, 3H). Compound 221: mp 105-107° C.; MS (ES⁺ calculated:166.18; found: 168.09 M+H). HPLC (900% purity, retention time 3.641minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 8.04 (s, 1H), 5.51 (s,2H), 4.00 (t, J=5 Hz, 2H), 3.60 (t, J=5 Hz, 2H), 33.29 (s, 3H).

Compound 222 3-Amino-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acidamide

Compound 221 was reacted with sulfuric acid to afford LC as a whitesolid (100%). Compound 222: MS (ES⁺ calculated: 184.20; found: 185.64M+H). HPLC (92% purity, retention time 2.138 minutes—Method A); ¹H NMR(400 MHz, DMSO-d⁶): δ 7.87 (s, 1H), 7.20 (br s, 1H), 6.69 (br s, 1H),5.33 (s, 2H), 3.97 (t, J=5 Hz, 2H), 3.60 (t, J=5 Hz, 2H), 3.22 (s, 3H).

Compound 2232-(2-Methoxyethyl)-2,7-dihydropyrazolo[3,4-d]pyrimidine-4,6-dione

Compound 222 was reacted with urea to afford a white solid. Yield:81%.Compound 223: mp 295-302° C.; MS (ES⁺ calculated: 210.19; found: 211.20M+). HPLC (90% purity, retention time 2.833 minutes—Method B); ¹H NMR(400 MHz, DMSO-d⁶): δ 11.06 (br s, 1H), 10.64 (br s, 1H), 8.28 (s, 1H),4.25 (t, J=5 Hz, 2H), 3.69 (t, J=5 Hz, 2H), 3.23 (s, 3H).

Compound 2244,6-Dichloro-2-(2-methoxyethyl)-2H-pyrazolo[3,4-d]pyrimidine

Compound 223 was reacted with phosphorus oxychloride to afford a whitesolid. Yield: 83%. Compound 224: MS (ES⁺ calculated: 247.09; found:247.97 M+). HPLC (94% purity, retention time 7.685 minutes—Method B); ¹HNMR (400 MHz, DMSO-d⁶): δ 9.03 (s, 1H), 4.66 (t, J=5 Hz, 2H), 3.86 (t,J=5 Hz, 2H), 3.24 (s, 3H).

Example 225 5-Bromo-3-[6-chloro-2-(2-methoxy-ethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

5-bromooxindole was condensed with Compound 224 to afford an orangesolid. Yield: 93%. Example 225: mp>300° C.; MS (ES⁺ calculated: 422.67;found: 423.90 M+H). HPLC (96% purity, retention time 11.474minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 10.48 (br s, 1H), 9.26(br s, 1H), 8.26 (br s, 1H), 7.16 (m, 1H), 6.72 (m, 1H), 4.46 (m, 2H),3.77 (m, 2H), 3.27 (s, 3H).

Example 2265-Bromo-3-[2-(2-methoxy-ethyl)-6-(3-methylamino-propylamino)-2H-pyrazolo[3,4-d]pyrimdin-4-yl]-1,3-dihydro-indol-2-one

Example 225 was reacted with N-(3-aminopropyl)-N-methylcarbamicacid-t-butyl ester. The product obtained by filtration from theethanolic solution was taken up into 4 mL 4N hydrochloric acid:dioxaneand stirred at room temperature for one hour. The reaction wasconcentrated and the solid was triturated with ethyl ether to affordafter filtering 28 mg (77%) of a yellow solid—isolated as thehydrochloride salt. Example 226: mp 232-6° C.; MS (ES⁺ calculated:474.36; found: 475.88 M+H). HPLC (85% purity, retention time 7.465minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 10.05 (br s, 1H), 9.42(br s, 1H), 9.00 (br s, 1H), 8.72 (br s, 2H), 8.06 (br s, 1H), 7.18 (brs, 1H), 6.72 (br s, 1H), 4.37 (m, 2H), 3.76 (m, 2H), 3.56 (m, 2H), 3.26(br s, 3H), 2.97 (m, 2H), 2.52 (m, 3H), 2.06 (m, 2H).

Example 2275-Bromo-3-[2-(2-methoxy-ethyl)-6-(2-piperidin-4-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 225 was reacted with 4-aminoethyl-1-N—BOC piperidine to affordafter removal of the BOC group a yellow solid—the hydrochloride salt.Yield:74%. Example 227: mp 248-51° C.; MS (ES⁺ calculated: 514.43;found: 515.92 M+H). HPLC (97% purity, retention time 7.507minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 11.53 (br s, 1H), 10.08(br s, 1H), 9.37 (br s, 1H), 8.70 (br s, 1H), 8.39 (br s, 1H), 7.20 (brs, 1H), 7.07 (br s, 1H), 6.70 (br s, 1H), 4.34 (m, 2H), 3.73 (s, 3H),3.50 (m, 2H), 2.81 (m, 2H), 1.87 (m, 2H), 1.70 (m, 1H), 1.60 (m, 2H),1.34 (m, 2H).

Example 2285-Bromo-3-[2-(2-methoxy-ethyl)-6-(2-piperidin-3-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 225 was reacted with 3-aminoethyl-1-N—BOC piperidine to affordafter removal of the BOC group a yellow solid—the hydrochloride salt.Yield:59%. Example 228: mp 270-3° C.; MS (ES⁺ calculated: 514.43; found:515.92 M+H). HPLC (100% purity, retention time 7.674 minutes—Method B);¹H NMR (400 MHz, DMSO-d⁶): δ 11.03 (br s, 1H), 10.08 (br s, 1H), 9.41(br s, 1H), 8.71 (br s, 1H), 8.46 (br s, 1H), 7.20 (br s, 1H), 7.08 (brs, 1H), 6.73 (br s, 1H), 4.80-1.10 (m, 17H), 3.74 (s, 3H).

Example 2295-Bromo-3-[6-(2-dimethylamino-ethylamino)-2-(2-methoxy-ethyl)-2H-pyrazolo[3,4-d]pyrimdin-4-yl]-1,3-dihydro-indol-2-one

Example 225 was reacted with N,N-dimethylethylenediamine to afford ayellow solid. Yield:65%. Example 229: mp 291-2° C.; MS (ES⁺ calculated:474.36; found: 475.84 M+H). HPLC (95% purity, retention time 7.827minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 10.80 (br s, 1H), 9.95(br s, 1H), 9.38 (s, 1H), 8.47 (br s, 1H), 6.98 (d, J=8 Hz, 1H), 6.64(d, J=8 Hz, 1H), 4.30 (m, 2H), 3.72 (m, 2H), 3.56 (m, 2H), 3.26 (s, 3H),2.60 (m, 2H), 2.24 (s, 6H).

Example 2305-Bromo-3-[6((S)-2-hydroxy-propylamino)-2-(2-methoxy-ethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 225 was reacted with (S)-2-hydroxy-1-aminopropane to afford ayellow solid. Yield:82%. Example 230: mp>300° C.; MS (ES⁺ calculated:461.32; found: 462.79 M+H). HPLC (94% purity, retention time 8.225minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 11.16 (br s, 1H), 10.00(s, 1H), 9.39 (s, 1H), 8.50 (s, 1H), 6.98 (d, J=8 Hz, 1H), 6.63 (d, J=8Hz, 1H), 4.97 (br s, 1H), 4.41 (m, 1H), 4.30 (m, 2H), 3.90 (br s, 1H),3.76 (m, 1H), 3.68 (m, 2H), 3.23 (s, 3H), 1.20 (d, J=8 Hz, 3H).

Example 2315-Bromo-3-[6-((R)-2-hydroxy-propylamino)-2-(2-methoxy-ethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 225 was reacted with (R)-2-hydroxy-1-aminopropane to afford ayellow solid. Yield:64%. Example 231: mp>300° C.; MS (ES⁺ calculated:461.32; found: 462.79 M+H). HPLC (98% purity, retention time 8.242minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 11.10 (br s, 1H), 9.96(s, 1H), 9.40 (s, 1H), 8.48 (s, 1H), 6.98 (d, J=8 Hz, 1H), 6.63 (d, J=8Hz, 1H), 4.97 (br s, 1H), 4.46 (m, 1H), 4.31 (m, 2H), 3.92 (br s, 1H),3.77 (m, 1H), 3.72 (m, 2H), 3.24 (s, 3H), 1.19 (d, J=8 Hz, 3H).

Example 2325-Bromo-3-{2-(2-methoxy-ethyl)-6-[(pyridin-3-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydro-indol-2-one

Example 225 was reacted with 3-aminomethylpyridine to afford a yellowsolid. Yield: 65%. Example 232: mp 300-301° C.; MS (ES⁺ calculated:494.35; found: 495.82 M+H). HPLC (89% purity, retention time 7.618minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 10.87 (s, 1H), 10.01 (s,1H), 9.44 (s, 1H), 8.70-8.40 (m, 4H), 7.37 (m, 1H), 6.96 (m, 1H), 6.60(m, 1H), 4.80 (m, 2H), 4.34 (m, 2H), 3.77 (m, 2H), 3.24 (s, 3H).

Example 2335-Bromo-3-[6-(3-dimethylamino-propylamino)-2-(2-methoxy-ethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Compound 225 was reacted with N,N-dimethylpropylenediamine to afford ayellow solid. Yield:58%. Example 233: mp 297-8° C.; MS (ES⁺ calculated:488.39; found: 489.89 M+H). HPLC (94% purity, retention time 7.519minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 10.80 (s, 1H), 9.90 (s,1H), 9.40 (s, 1H), 8.52 (s, 1H), 67.0 (d, J=8 Hz, 2H), 6.68 (d, J=8 Hz,1H), 4.30 (m, 2H), 3.74 (m, 2H), 3.50 (m, 2H), 3.35 (m, 2H), 3.21 (s,3H), 2.27 (s, 6H), 1.82 (m, 2H).

Example 2345-Bromo-3-[2-(2-methoxy-ethyl)-6-(2-morpholin-4-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 225 was reacted with N-aminoethylmorpholine to afford a yellowsolid. Yield: 55%. Example 234: mp>300° C.; MS (ES⁺ calculated: 516.40;found: 517.82 M+H). HPLC (97% purity, retention time 8.150minutes—Method B); ¹HNMR (400 MHz, DMSO-d⁶): δ 10.82 (s, 1H), 10.00 (s,1H), 9.42 (s, 1H), 8.48 (br s, 1H), 7.02 (m, 2H), 6.62 (m, 1H), 4.32 (m,2H), 3.72 (m, 2H), 3.63 (m, 8H), 3.31 (m, 5H), 2.70 (m, 2H).

Example 2355-Bromo-3-[2-(2-methoxy-ethyl)-6-(2-methoxy-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 225 was reacted with 2-methoxyethylamine to afford a yellowsolid. Yield: 100%. Example 235: mp>300° C.; MS (ES⁺ calculated: 461.32;found: 462.77 M+H). HPLC (97% purity, retention time 8.518minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 11.20 (br s, 1H), 10.00(s, 1H), 9.40 (s, 1H), 8.46 (s, 1H), 6.96 (d, J=8 Hz, 2H), 6.64 (d, J=8Hz, 1H), 4.30 (m, 2H), 3.70 (m, 2H), 3.68 (m, 2H), 3.50 (m, 2H), 3.29(s, 3H), 3.22 (s, 3H).

Example 236 5-Bromo-3-[6-chloro-2-(2-ethoxy-ethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

To a stirring solution of 5-bromooxindole (163 mg, 0.769 mmol) andanhydrous THF (7 mL) in a 15 mL flask at −78° C. was added LDA (0.769mL, 1.538 mmol). The reaction mixture was stirred for 15 min beforeadding the Compound 210 (200 mg, 0.769 mmol) as a solid. Following anadditional 15 min at −78° C., the reaction was allowed to warm to roomtemperature and stirred overnight. The reaction mixture was concentratedto dryness, taken up into MeOH and concentrated onto silica gel andpumped dry before subjecting it to flash chromatography on silica gel(gradient elution: 1-10% methanol: dichloromethane) to afford 228 mg(68%) of a yellow solid after concentrated and was triturated in ether.Example 236: mp 260-263° C.; MS (ES⁺ calculated: 436.70; found: 437.92M+H). HPLC (91%) purity, retention time 4.946 minutes—Method C); ¹H NMR(400 MHz, DMSO-d6) δ 10.50 (br s, 1H), 9.3 (br s, 1H), 8.3 (br s, 1H),7.17 (d, J=8 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 4.47 (s, 2H), 3.80 (m, 2H),3.45 (m), 2.62 (s, 6H) 1.08 (m, 3).

Example 2375-Bromo-3-[6-(2-dimethylamino-ethylamino)-2-(2-ethoxy-ethyl)2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 212, Example 236 (30 mg, 0.0687mmol) and N,N-dimethylaminoethylamine (60.5 μL, 0.687 mmol) were heatedin 1 mL EtOH at 130° C. in microwave for 10 min. Upon cooling, theproduct precipitated in the reaction tube. The resulting solid wasfiltered and pumped dry to afford 24 mg (71%) of a yellow solid. Example237: mp 247-251° C.; MS (ES⁺ calculated: 488.39; found: 489.4 M+H). HPLC(94%) purity, retention time 3.410 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 9.99 (s, 1H), 9.44 (s, 1H), 8.63 (s, 1H), 7.02 (d, 1H), 6.67(d, 1H), 4.31 (t, 2H), 3.76 (m, 2H), 3.61 (br s, 1H), 3.42 (m), 2.33 (s,2H) 2.18 (s, 1H), 0.86 (m, 9H).

Example 2385-Bromo-3-[2-(2-ethoxy-ethyl)-6-((S)-2-hydroxy-propylamno)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 212, Example 236 (30 mg, 0.0687mmol) and (S)-(+)-1-amino-2-propanol (54 μL, 0.687 mmol) were heated in1 mL EtOH at 130° C. in microwave for 10 min. Upon cooling, the productprecipitated in the reaction tube. The resulting solid was filtered andpumped dry to afford 26 mg (80%) of a yellow solid. Example 238: mp297-299° C.; MS (ES⁺ calculated: 475.35; found: 475.2 M+H). HPLC (94%)purity, retention time 2.785 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 10.00 (s, 1H), 9.44 (s, 1H), 8.61 (s, 1H), 7.00 (d, 1H), 6.67(d, 1H), 4.97 (br s, 1H), 4.31 (t, 2H), 3.76 (m, 2H), 3.61 (br s, 1H),3.43 (m), 1.22 (d, 3H), 1.07 (m).

Example 2395-Bromo-3-[2-(2-ethoxy-ethyl)-6-((R)-2-hydroxy-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 212, Example 236 (30 mg, 0.0687mmol) and (R)-(−)-1-amino-2-propanol (54 μL, 0.687 mmol) were heated in1 mL EtOH at 130° C. in microwave for 10 min. Upon cooling, the productprecipitated in the reaction tube. The resulting solid was filtered andpumped dry to afford 28 mg (86%) of a yellow solid. Example 239: mp298-300° C.; MS (ES⁺ calculated: 475.35; found: 475.2 M+H). HPLC (95%)purity, retention time 2.783 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 10.00 (s, 1H), 9.44 (s, 1H), 8.61 (s, 1H), 7.00 (d, 1H), 6.67(d, 1H), 4.97 (br s, 1H), 4.31 (t, 2H), 3.76 (m, 2H), 3.61 (br s, 1H),3.43 (m), 1.22 (d, 3H), 1.07 (m).

Example 2405-Bromo-3-[2-(2-ethoxy-ethyl)-6-(2-morpholin-4-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Using the procedure outlined for Example 212, Example 236 (30 mg, 0.0737mmol) and N-(2-aminoethyl)morpholine (90 μL, 0.737 mmol) were heated in1 mL EtOH at 130° C. in microwave for 10 min. Upon cooling, the productprecipitated in the reaction tube. The resulting solid was filtered andpumped dry to afford 29 mg (80%) of a yellow solid. Example 240: mp276-278° C.; MS (ES⁺ calculated: 530.43; found: 530.61 M+H). HPLC (96%)purity, retention time 2.757 minutes—Method C); ¹H NMR (400 MHz,DMSO-d₆) δ 10.00 (s, 1H), 9.45 (s, 1H), 8.53 (s, 1H), 7.00 (d, 1H), 6.87(m, 1H), 6.66 (d, J=8 Hz, 1H), 4.32 (t, J=7 Hz, 2H), 3.77 (t, 1H), 3.64(m, 8H), 2.66 (m, 2H), 1.83 (m, 4H), 1.07 (m, 3H).

The following Examples 241-254 in Table 4 were prepared according toprocedures disclosed herein including using methods generally known toone skilled in the art.

TABLE 4

Example R² X 241 H —NH—CH₂-4-Pyridyl 242 H —NH—(CH₂)₂-2-pyridyl 243 H—NH—CH₂—CH═CH₂ 244 H —NH—CH₂—CH(CH₃)₂ 245 H —NH—CH(CH₃)₂ 246 CF₃—NH—CH₂-4-pyridyl 247 CF₃ —NH—(CH₂)₂-2-pyridyl 248 CF₃ —NH—CH₂—CH═CH₂249 CF₃ —NH—CH₂—CH(CH₃)₂ 250 CF₃ —NH—CH(CH₃)₂ 251 CF₃ —NH—(CH₂)₂—N(CH₃)₂252 CF₃ —NH—(CH₂)₂—NH₂*HCl 253 CF₃ —NH—(CH₂)₃—NHCH₃*HCl 254 CF₃—NH—(CH₂)₃—NH₂*HCl

Example 2413-{2-Cyclopentyl-6-[(pyridin-4-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydro-indol-2-one

A mixture of Example 152 (40 mg, 0.11 mmol), in 4-aminomethylpyridine(119 mg, 1.1 mmol) and 2-methoxyethanol (2 mL) were heated to 130° C.for 5 h. The reaction was concentrated. The Example was purified via aflash silica gel column eluting with 5% to 10% methanol/methylenechloride. The most pure fractions were concentrated, treated with ethylether and filtered to give 23 mg (50%) of Example 241. Example 241:¹HNMR (400 MHz, DMSO-d₆) δ 13.9 (s, 1H), 10.7 (s, 1H), 8.6 (m, 2H), 8.4(m, 1H), 7.8 (m, 1H), 7.3 (m, 2H), 7.0 (m, 2H), 6.9 (m, 1H), 5.0 (m,1H), 4.8 (m, 1H), 4.6 (d, 2H), 1.6-2.2 (m, 8H); MS (m/e) 426 (M+1); HPLC(95%) purity, retention time 3.472 minutes—Method C; mp 198-200° C.

Example 2423-[2-Cyclopentyl-6-(2-pyridin-2-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Examples 242 was synthesized in a similar manner to Example 241 asdisclosed herein using the appropriate starting materials. Example 242:¹HNMR (400 MHz, DMSO-d₆) δ 13.7 (s, 1H), 10.7 (s, 1H), 8.8 (s, 1H), 8.6(m, 1H), 7.8 (m, 3H), 7.3 (m, 1H), 7.2 (m, 1H), 7.0 (m, 1H), 5.8 (s,2H), 5.0 (m, 1H), 3.7 (m, 2H), 3.1 (m, 2H), 1.6-2.2 (m, 8H); MS (m/e)440 (M+1); HPLC (99%) purity, retention time 3.397 minutes—Method C; mp246-248° C.

Example 2433-(6-Allylamino-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Examples 243 was synthesized in a similar manner to Example 241 asdisclosed herein using the appropriate starting materials. Example 243:¹HNMR (400 MHz, DMSO-d₆) δ 13.8 (s, 1H), 10.7 (s, 1H), 8.8 (s, 1H), 7.9(m, 1H), 7.7 (m, 1H), 6.7-7.0 (m, 4H), 5.9-6.1 (m, 1H), 5.0-5.3 (m, 2H),3.8 (m, 2H), 1.6-2.2 (m, 8H); MS (m/e) 375 (M+1); HPLC (99%) purity,retention time 4.082 minutes—Method C; mp>300° C.

Example 2443-(2-Cyclopentyl-6-isobutylamino-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Examples 244 was synthesized in a similar manner to Example 241 asdisclosed herein using the appropriate starting materials. Example 244:¹HNMR (400 MHz, DMSO-d₆) δ 13.7 (s, 1H), 10.7 (s, 1H), 8.7 (s, 1H), 7.7(m, 2H), 6.7-7.1 (m, 4H), 5.0 (m, 1H), 3.1 (m, 2H), 1.6-2.2 (m, 8H), 1.0(m, 6H); MS (m/e) 391 (M+1); HPLC (95%) purity, retention time 4.469minutes—Method C; mp 280-282° C.

Example 2453-(2-Cyclopentyl-6-isopropylamino-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Examples 245 was synthesized in a similar manner to Example 241 asdisclosed herein using the appropriate starting materials. Example 245:¹HNMR (400 MHz, DMSO-d₆) δ 13.6 (s, 1H), 10.7 (s, 1H), 8.7 (s, 1H), 7.7(d, 1H), 7.5 (d, 1H), 6.7-7.1 (m, 3H), 5.0 (m, 1H), 4.1 (m, 1H), 1.6-2.2(m, 8H), 1.2 (m, 6H); MS (m/e) 377 (M+1); HPLC (92%) purity, retentiontime 4.124 minutes—Method C; mp 303-305° C.

Example 2463-{2-Cyclopentyl-6-[(pyridin-4-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-5-trifluoromethyl-1,3-dihydro-indol-2-one

A mixture of Example 153 (40 mg, 0.095 mmol), in 4-Aminomethylpyridine(103 mg, 0.95 mmol) and 2-methoxyethanol (2 mL) were heated to 130° C.for 5 h. The reaction was concentrated. The Example was purified via aflash silica gel column eluting with 5% methanol/methylene chloride. Themost pure fractions were concentrated, treated with ethyl ether andfiltered to give 6 mg (13%) of Example 246. Example 246: ¹HNMR (400 MHz,DMSO-d₆) δ 11.7 (s, 1H), 10.3 (s, 1H), 9.5 (s, 1H), 8.5 (m, 3H), 7.5 (m,1H), 7.3 (m, 2H), 7.1 (m, 1H), 6.8 (d, 1H), 4.8 (m, 3H), 1.6-2.2 (m,8H); MS (m/e) 494 (M+1); HPLC (94%) purity, retention time 3.979minutes—Method C; mp>300° C.

Example 2473-[2-Cyclopentyl-6-(2-pyridin-2-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-trifluoromethyl-1,3-dihydro-indol-2-one

Example 247 was synthesized in a similar manner to Example 246 asdisclosed herein using the appropriate starting materials. Example 247:¹HNMR (400 MHz, DMSO-d₆) δ 11.4 (s, 1H), 10.3 (s, 1H), 9.5 (s, 1H), 8.7(s, 1H), 8.5 (d, 1H), 7.7 (m, 1H), 7.2-7.4 (m, 3H), 6.8-7.0 (m, 2H), 4.8(m, 1H), 3.9 (m, 2H), 3.2 (t, 2H), 1.6-2.2 (m, 8H); MS (m/e) 508 (M+1);HPLC (97%) purity, retention time 4.140 minutes—Method C; mp>300° C.

Example 2483-(6-Allylamino-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-trifluoromethyl-1,3-dihydro-indol-2-one

Example 248 was synthesized in a similar manner to Example 246 asdisclosed herein using the appropriate starting materials. Example 248:¹HNMR (400 MHz, DMSO-d₆) δ 11.6 (s, 1H), 10.3 (s, 1H), 9.5 (s, 1H), 8.7(s, 1H), 7.2 (d, 1H), 7.1 (m, 1H), 6.9 (m, 1H), 6.0 (m, 1H), 5.3 (d,1H), 5.1 (d, 1H), 4.8 (m, 1H), 4.2 (s, 2H), 1.6-2.2 (m, 8H); MS (m/e)443 (M+1); HPLC (99%) purity, retention time 4.965 minutes—Method C;mp>300° C.

Example 2493-(2-Cyclopentyl-6-isobutylamino-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-trifluoromethyl-1,3-dihydro-indol-2-one

Example 249 was synthesized in a similar manner to Example 246 asdisclosed herein using the appropriate starting materials. Example 249:¹HNMR (400 MHz, DMSO-d₆) δ 11.2 (s, 1H), 10.3 (s, 1H), 9.5 (s, 1H), 8.7(s, 1H), 7.2 (d, 1H), 6.9 (d, 1H), 6.8 (m, 1H), 4.8 (m, 1H), 3.4 (m,2H), 1.6-2.2 (m, 8H), 0.9 (d, 6H); MS (m/e) 459 (M+1); HPLC (99%)purity, retention time 5.305 minutes—Method C; mp 282-285° C.

Example 2503-(2-Cyclopentyl-6-isopropylamino-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-trifluoromethyl-1,3-dihydro-indol-2-one

Example 250 was synthesized in a similar manner to Example 246 asdisclosed herein using the appropriate starting materials. Example 250:¹HNMR (400 MHz, DMSO-d₆) δ 11.1 (s, 1H), 10.3 (s, 1H), 9.5 (s, 1H), 8.7(s, 1H), 7.2 (d, 1H), 6.9 (d, 1H), 6.7 (m, 1H), 4.8 (m, 1H), 4.4 (m,1H), 1.6-2.2 (m, 8H), 1.3 (d, 6H); MS (m/e) 445 (M+1); HPLC (97%)purity, retention time 4.973 minutes—Method C; mp 299-301° C.

Example 2513-[2-Cyclopentyl-6-(2-dimethylamino-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-trifluoromethyl-1,3-dihydro-indol-2-one

Example 251 was synthesized in a similar manner to Example 246 asdisclosed herein using the appropriate starting materials. Example 251:¹HNMR (400 MHz, DMSO-d₆) δ 10.3 (s, 1H), 9.5 (s, 1H), 8.7 (s, 1H), 7.2(d, 1H), 6.9 (d, 1H), 4.8 (m, 1H), 3.4 (m, 2H), 2.9 (t, 2H), 2.4 (t,2H), 2.2 (s, 6H), 1.6-2.2 (m, 8H); MS (m/e) 474 (M+1); HPLC (91%)purity, retention time 4.076 minutes—Method C; mp 211-213° C.

Example 2523-[6-(2-Amino-ethylamino)-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-trifluoromethyl-1,3-dihydroindol-2-onehydrochloride salt

A mixture of Example 153 (63 mg, 0.15 mmol), N-BOC-ethylenediamine (0.24gm, 1.5 mmol), and ethanol (1 mL) were heated in a microwave at 130° C.for 10 minutes. The reaction was cooled to room temperature and aprecipitate formed. The solid was filtered, washed with ethanol andethyl ether to give 56 mg (68%) of the intermediate. Next, the materialwas stirred in 4N HCl in 1,4-dioxane (2 mL). After 1 hour the reactionwas concentrated. The solid was treated with ether and filtered to give35 mg (70%) of Example 252. Example 252: ¹HNMR (400 MHz, DMSO-d₆) δ 12.0(s, 1H), 10.3 (s, 1H), 9.5 (s, 1H), 8.6 (s, 1H), 8.0 (m, 2H), 7.4 (m,2H), 6.9 (m, 1H), 4.8 (m, 1H), 3.7 (m, 2H), 3.2 (m, 2H), 1.6-2.2 (m,8H); MS (m/e) 446 (M+1); HPLC (99%) purity, retention time 3.917minutes—Method C; mp 290-293° C.

Example 253 3-[2-Cyclopentyl-6-(3-methylamino-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-trifluoromethyl-1,3-dihydro-indol-2-onehydrochloride salt

Example 253 was synthesized in a similar manner to Example 252 asdisclosed herein using the appropriate starting materials. Example 253:¹HNMR (400 MHz, DMSO-d₆) δ 11.8 (bs, 1H), 10.3 (bs, 1H), 9.5 (bs, 1H),8.8 (s, 1H), 8.7 (m, 1H), 7.4 (m, 1H), 7.2 (m, 1H), 6.9 (m, 1H), 4.8 (m,1H), 3.6 (m, 2H), 3.0 (m, 4H), 1.6-2.2 (m, 11H); MS (m/e) 475 (M+1);HPLC (99%) purity, retention time 3.977 minutes—Method C; mp 260-262° C.

Example 2543-[6-(3-Amino-propylamino)-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-trifluoromethyl-1,3-dihydro-indol-2-onehydrochloride salt

Example 254 was synthesized in a similar manner to Example 252 asdisclosed herein using the appropriate starting materials. Example 254:¹HNMR (400 MHz, DMSO-d₆) δ 11.9 (bs, 1H), 10.3 (bs, 1H), 9.5 (bs, 1H),8.8 (s, 1H), 8.1 (m, 2H), 7.7 (m, 1H), 7.3 (m, 1H), 6.9 (m, 1H), 4.8 (m,1H), 3.6 (m, 2H), 3.0 (m, 4H), 1.6-2.2 (m, 8H); MS (m/e) 460 (M+1); HPLC(97%) purity, retention time 3.850 minutes—Method C; mp 304-306° C.

Compound 255 and 256 5-Amino-1-isobutyl-1H-pyrazole-4-carbonitrile3-Amino-1-isobutyl-1H-pyrazole-4-carbonitrile

3-Amino-4-pyrazolecarbonitrile 1 (Aldrich, 24.0 g, 0.222 mole),1-bromo-2-methyl-propane (Lancaster, 36.48 g, 0.266 mole) and anhydrouspotassium carbonate (Acros, 36.8 g, 0.266 mole) were suspended in 240 mLreagent grade acetonitrile and heated at 80° C. under nitrogen for 22hours. LC/MS indicated 1 remained. Therefore, added an additional 3 mL(0.027 mole) 1-bromo-2-methylpropane and 4.25 g (0.031 mole) K₂CO₃.After 24 hours, the reaction was filtered and the filtrate concentratedin vacuo. The solid was stirred in 250 mL of water for 3.5 hours at roomtemp. The solid was filtered, washed with 50 mL diethyl ether, and driedto yield 16.28 g (45%) of a tan powder which was seen by ¹H NMR tocontain a mixture of 255 and 256 in approximately a 2:1 ratio. Thismixture was used without further purification. Mixture of 255 and 256:mp 91.3-106; MS (ES⁺ calculated: 164.21; found: 165.28 M+H). HPLC (99%purity, retention times 6.920 and 7.086 minutes—Method B); ¹H NMR (400MHz, DMSO-d₆) δ 8.05 and 7.51 (s, 1H), 6.50 and 5.49 (s, 2H), 3.68 (t,2H), 2.05 (m, 1H), 0.82 and 0.81 (d, 6H).

Compound 257 and 258 5-Amino-1-isobutyl-1H-pyrazole-4-carboxylic acidamide 3-Amino-1-isobutyl-1H-pyrazole-4-carboxylic acid amide

To concentrated sulfuric acid (Fisher, 48 mL) at 0° C. was added 229 and230 (5.89 g, 36.0 mmol) in small portions. The reaction was allowed towarm to room temperature and was stirred over 4.25 hours. The viscousreaction was added slowly (violent) to 240 mL concentrated ammoniumhydroxide solution (Fisher) over 25 minutes. Added 300 mL of water tothe mixture and extracted with EtOAc, dried over MgSO₄, filtered, andconcentrated in vacuo to afford 5.48 g (84%) of an off-white solid whichwas seen by ¹H NMR to contain a mixture of 257 and 258 in approximatelya 2:1 ratio. Mixture of 257 and 258: mp 154-157.8° C.; MS (ES⁺calculated: 182.23; found: 183.23 M+H). HPLC (99% purity, retention time6.498 minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ 7.84 and 7.61 (s,1H), 7.10 (br s, 1H), 6.70 (br s, 1H), 6.14 and 5.31 (s, 1H), 3.64 (m,2H), 2.05 (m, 1H), 0.83 (d, 6H).

Compound 259 2-Isobutyl-2H-pyrazolo[3,4-d]pyrimidine-4,6-diol

Heated 1.575 g (8.64 mmol) and 4.725 g (78.7 mmol) urea at 200° C. in aselade tube for 3.5 hours in a sealed tube. The mixture was cooled to100° C., and 34 mL water was added. The mixture was refluxed at 100° C.for 20 hours. The reaction was cooled to room temperature, additionalwater was added, and the product was extrated using ethyl acetate. Theorganic layer was dried with MgSO₄, filtered, and conc. in vacuo to give989 mg (55%) of a white solid which was seen by ¹H NMR to contain only259: mp 327.5-330° C.; MS (ES⁺ calculated: 208.22; found: 209.25 M+H).HPLC (99% purity, retention time 5.631 minutes—Method B); ¹H NMR (400MHz, DMSO-d₆) δ 11.32 (s, 1H), 10.64 (s, 1H), 8.32 (s, 1H), 3.90 (d,2H), 2.12 (m, 1H), 0.84 (d, 6H).

Compound 260 4,6-Dichloro-2-isobutyl-2H-pyrazolo[3,4-d]pyrimidine

Compound 259 (500 mg, 2.4 mmol) was dissolved in phosphorus oxychloride(Acros, 8 mL) and the mixture was refluxed under argon at 110° C. for29.5 hours. Excess phosphorus oxychloride was removed in vacuo and icethen water was added to the dark orange syrup. Next, 10N NaOH was addeduntil the pH equaled 14. The product was then extracted with methylenechloride, dried over MgSO₄, filtered and conc. in vacuo. afford a whitesolid which was purified by flash chromatography on silica gel elutingwith 500:11 dichloromethane:methanol to afford 388 mg (25%) of a whitesolid. Compound 260: MS (ES⁺ calculated: 245.11; found: 245.40 M). HPLC(99%) purity, retention time 10.794 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆) δ 9.05 (s, 1H), 4.34 (d, 2H), 2.33 (m, 1H), 0.90 (d, 6H).

Example 2615-Chloro-3-(6-chloro-2-isobutyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

To 5-cyanooxindole (CombiBlocks, 238 mg, 1.42 mmol) in 7.0 mL anhydrousTHF under argon at −78° C. was added lithium diisopropylamine (Acros,1.42 mL of a 2.0M solution in THF/heptane, 2.84 mmol). The solution wasstirred for fifteen minutes at which point compound 260 (348 mg, 1.42mmol) was added. The reaction was stirred for fifteen minutes, externalcooling was removed, and the reaction was allowed to warm to roomtemperature. After 2.75 hours the solution was quenched with water. Thereaction was concentrated in vacuo and the residue was purified by flashchromatography on silica gel eluting with 99:1 dichloromethane:methanolto afford 125 mg of Example 261 as an orange solid: mp 284° C. (dec); MS(ES⁺ calculated: 376.25; found: 376.62 M). HPLC (95%) purity, retentiontime 13.170 minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (br s,1H), 9.28 (s, 1H), 8.09 (s, 1H), 7.06 (d, 1H), 6.84 (d, 1H), 4.15 (d,2H), 3.33 (br s, 1H), 2.21 (m, 1H), 0.90 (d, 6H).

Example 2625-Bromo-3-(6-chloro-2-isobutyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

To 5-bromooxindole (CombiBlocks, 216 mg, 1.02 mmol) in 7.0 mL anhydrousTHF under argon at −78° C. was added lithium diisopropylamine (Acros,1.02 mL of a 2.0M solution in THF/heptane, 2.04 mmol) over 4 minutes.The solution was stirred for thirty minutes at which point a solution ofcompound 260 (250 mg, 1.02 mmol) in 3.13 mL dry THF was added over 3minutes. The reaction was stirred for twenty-three minutes, the externalcooling was removed, and the reaction was permitted to warm to roomtemperature. After 3 hours the solution was quenched with water. Thereaction was concentrated in vacuo and the residue was purified by flashchromatography on silica gel eluting with 98:2 then 95:5dichloromethane:methanol to afford Example 262 as a burnt orange solidin two separate lots totaling 183 mg (43%): m.p. 295° C. (decomp.); MS(ES⁺ calculated: 420.70; found: 421.94 M+H). HPLC (89% purity, retentiontime 13.399 minutes—Method B); ¹H NMR (400 MHz, DMSO-d₆): δ 10.49 (br s,1H), 9.29 (br s, 1H), 8.26 (br s, 1H), 7.18 (d, 1H), 6.79 (d, 1H), 4.14(d, 2H), 3.49 (br s, 1H), 2.20 (m, 1H), 0.89 (d, 6H).

Example 2635-Bromo-3-[2-isobutyl-6-(2-methoxy-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

m.p. 294-296.8° C.; MS (ES⁺ calculated: 459.35; found: 459.67 M+H). HPLC(99% purity, retention time 10.803 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 11.23 (br s, 1H), 9.99 (s, 1H), 9.40 (s, 1H), 8.49 (s, 1H),7.01 (d, 1H), 6.68 (d, 1H), 3.99 (d, 2H), 3.66 (m, 4H), 3.48 (m, 1H),3.38 (s, 3H), 2.17 (m, 1H), 0.88 (d, 6H).

Example 2645-Bromo-3-[2-isobutyl-6-(2-morpholin-4-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

m.p. 282-287° C.; MS (ES⁺ calculated: 514.43; found: 514.63 M+H). HPLC(99% purity, retention time 9.976 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 11.62 (br s, 1H), 9.98 (s, 1H), 9.40 (s, 1H), 8.53 (s, 1H),7.00 (d, 1H), 6.67 (d, 1H), 3.99 (d, 2H), 3.64 (m, 6H), 3.29 (m, 1H),2.66 (t, 2H), 2.45 (m, 4H), 2.16 (m, 1H), 0.88 (d, 6H).

Example 2655-Bromo-3-[2-isobutyl-6-(3-morpholin-4-yl-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

m.p. 271-274° C.; MS (ES⁺ calculated: 528.46; found: 528.58 M+H). HPLC(99% purity, retention time 9.547 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 11.40 (br s, 1H), 9.97 (s, 1H), 9.40 (s, 1H), 8.55 (s, 1H),7.00 (d, 1H), 6.67 (d, 1H), 3.99 (d, 2H), 3.57 (m, 6H), 3.29 (s, 1H),2.38 (s, 6H), 2.16 (m, 1H), 1.84 (m, 2H), 0.88 (d, 6H).

Example 2675-Bromo-3-[2-isobutyl-6-(3-methylamino-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

m.p. 240-259° C.; MS (ES⁺ calculated (free base)-472.39; found: 472.60M+H). HPLC (99% purity, retention time 9.265 minutes—Method B); ¹H NMR(400 MHz, DMSO-d₆): δ10.11 (br s, 1H), 9.32 (br s, 1H), 8.83 (br s, 2H),8.48 (br s, 1H), 7.50 (br s, 1H), 7.09 (br s, 1H), 6.77 (br s, 1H), 4.04(br s, 2H), 3.56 (br s, 2H), 3.02 (br s, 1H), 2.55 (t, 3H), 2.19 (m,1H), 2.03 (br s, 2H), 0.89 (d, 6H).

Example 2685-Bromo-3-[6-(2-dimethylamino-ethylamino)-2-isobutyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

m.p. 261-264.5° C.; MS (ES⁺ calculated: 472.39; found: 472.64 M+H). HPLC(99% purity, retention time 9.577 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 9.97 (s, 1H), 9.40 (s, 1H), 8.51 (s, 1H), 6.99 (d, 1H), 6.83(br s 1H), 6.67 (d, 1H), 3.97 (d, 2H), 3.59 (s, 2H), 3.28 (m, 2H), 2.61(s, 1H), 2.27 (s, 6H), 2.15 (s, 1H), 0.89 (d, 6H).

Example 2695-Bromo-3-[6-(3-dimethylamino-propylamino)-2-isobutyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

m.p. 250.5-254° C.; MS (ES⁺ calculated: 486.42; found: 486.62 M+H). HPLC(99% purity, retention time 9.427 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 9.92 (s, 1H), 9.40 (s, 1H), 8.54 (s, 1H), 7.16 (m, 1H), 6.98(d, 1H), 6.66 (d, 1H), 3.99 (d, 2H), 3.50 (br s, 2H), 3.31 (br s, 2H),2.24 (s, 6H), 2.20 (m, 2H), 1.82 (m, 2H), 0.88 (d, 6H).

Example 2705-Chloro-3-[6-(2-dimethylamino-ethylamino)-2-isobutyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

m.p. 264-265.5° C.; MS (ES⁺ calculated: 427.94; found: 428.45 M+H). HPLC(96% purity, retention time 9.183 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 9.89 (s, 1H), 9.40 (s, 1H), 8.38 (s, 1H), 6.83 (d, 1H), 6.76(m, 1H), 6.70 (d, 1H), 3.98 (d, 2H), 3.57 (br s, 2H), 3.27 (m, 2H), 2.59(s, 1H), 2.26 (s, 6H), 2.20 (s, 1H), 0.88 (d, 6H).

Example 2715-Chloro-3-[2-isobutyl-6-(3-morpholin-4-yl-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

m.p. 263-265.5° C.; MS (ES⁺ calculated: 484.01 found: 484.44 M+H). HPLC(99% purity, retention time 9.391 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 11.35 (br s, 1H), 9.95 (s, 1H), 9.41 (s, 1H), 8.40 (s, 1H),6.88 (dd, 1H), 6.71 (d, 1H), 3.99 (d, 2H), 3.60 (s, 4H), 3.32 (m, 1H),2.50 (m, 6H), 2.45 (t, 2H), 2.17 (s, 1H), 1.83 (m, 2H), 0.88 (d, 6H).

Example 2725-Chloro-3-[2-isobutyl-6-(2-methoxy-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

m.p. 286-289° C.; MS (ES⁺ calculated: 414.90; found: 415.48 M+H). HPLC(99% purity, retention time 10.583 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 11.22 (br s, 1H), 9.98 (s, 1H), 9.41 (s, 1H), 8.34 (s, 1H),6.91 (d, 1H), 6.71 (d, 1H), 3.99 (d, 2H), 3.67 (s, 2H), 3.64 (d, 2H),3.48 (m, 1H), 3.33 (s, 3H), 2.17 (m, 1H), 0.88 (d, 6H).

Example 273 5-Chloro-3-(6-chloro-2-isobutyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

m.p. 284 (decomp.)° C.; MS (ES⁺ calculated: 376.25; found: 376.62 M+H).HPLC (95% purity, retention time 13.170 minutes—Method B); ¹H NMR (400MHz, DMSO-d₆): δ 10.53 (br s, 1H), 9.28 (br s, 1H), 8.09 (br s, 1H),4.15 (d, 2H), 3.33 (br s, 1H), 2.21 (m, 1H), 0.89 (d, 6H).

Example 2753-{6-[(1-Butyl-piperidin-4-ylmethyl)-amino]-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-5-chloro-1,3-dihydro-indol-2-one

m.p. 83-201° C.; MS (ES⁺ calculated: 522.10; found: 522.47 M+H). HPLC(95% purity, retention time 10.638 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 9.93 (br s, 1H), 9.49 (br s, 1H), 8.37 (br s, 1H), 6.90 (m,1H), 6.86 (d, 1H), 6.71 (d, 1H), 4.78 (s, 1H), 3.49-3.17 (m, 3H),2.96-2.71 (m, 3H), 2.25 (s, 2H), 2.12 (s, 2H), 1.96 (s, 2H), 1.85-1.57(m, 7H), 1.38-1.10 (m, 6H).

Example 276N-{2-[4(5-Chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)-2-cyclopentyl-2H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethyl}-acetamide

m.p. 209-226° C.; MS (ES⁺ calculated: 453.94; found: 454.52 M+H). HPLC(93.5% purity, retention time 10.332 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 11.46 (br s), 10.81 (s), 9.96 (s), 9.49 (s), 8.67 (s), 8.35(s), 8.01-7.83 (m, 5H), 7.04-6.72 (m, 2H), 5.01 (m), 4.80 (m), 3.55 (s,1H), 3.37 (m, 1H), 3.07 (m, 4H), 2.13 (s, 1H), 1.95 (s, 1H), 1.82 (s,7H).

Example 2775-Chloro-3-[2-cyclopentyl-6-(2-methyoxy-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

m.p. 249-259° C.; MS (ES⁺ calculated: 426.91; found: 427.46 M+H). HPLC(98.5% purity, retention time 11.161 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 11.37 (br s, 1H), 9.97 (s, 1H), 9.49 (s, 1H), 6.88 (dd, 1H),6.71 (d, 1H), 5.00 and 4.80 (m, 1H), 3.68-3.62 (m, 2H), 3.52-3.43 (m,2H), 3.32 (s, 3H), 2.97 (t, 1H), 2.13 (m, 2H), 1.96 (m, 2H), 1.82 (m,2H), 1.69 (m, 2H).

Example 2785-Chloro-3-[2-cyclopentyl-6-(3-morpholin-4-yl-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indole-2-one

m.p. 250-254.5° C.; MS (ES⁺ calculated: 496.02; found: 496.44 M+H). HPLC(99% purity, retention time 9.988 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 9.93 (s, 1H), 9.48 (s, 1H), 8.39 (s, 1H), 6.98 (dd, 1H),6.86 (d, 1H), 6.70 (d, 1H), 4.80 (m, 1H), 3.61 (m, 4H), 3.50 (m, 1H),3.29 (m, 2H), 2.45 (t, 1H), 2.37 (m, 5H), 2.13 (m, 2H), 1.95 (m, 2H),1.83 (m, 4H), 1.71 (m, 2H).

Example 2795-Chloro-3-[2-cyclopentyl-6-(2-pyridin-3-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

m.p. 277-281° C.; MS (ES⁺ calculated: 473.97; found: 474.37 M+H). HPLC(99% purity, retention time 9.571 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 11.39 (br s, 1H), 9.98 (s, 1H), 9.50 (s, 1H), 8.51 (m, 1H),8.42 (m, 2H), 7.72 (m, 1H), 7.33 (m, 1H), 6.99 (dd, 1H), 6.80 (dd, 1H),4.82 (m, 1H), 3.78 (m, 2H), 3.57 (m, 0.5H), 3.30 (m, 2H), 3.02 (m,0.5H), 2.13 (m, 2H), 1.95 (m, 2H), 1.82 (m, 2H), 1.68 (m, 2H).

Example 2805-Chloro-3-(2-cyclopentyl-6-isobutylamino-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

m.p. 282-286° C.; MS (ES⁺ calculated: 424.94; found: 425.45 M+H). HPLC(99% purity, retention time 12.303 minutes—Method B); ¹H NMR (400 MHz,DMSO-d₆): δ 11.20 (br s, 1H), 9.96 (s, 1H), 9.49 (s, 1H), 8.42 (s, 1H),3.35 (m, 1H), 2.13 (m, 2H), 2.02 (m, 4H), 1.82 (m, 2H), 1.68 (m, 2H).

Compound 281 and 282 3-Amino-1-pentyl-1H-pyrazole-4-carbonitrile5-Amino-1-pentyl-1H-pyrazole-4-carbonitrile

3-Amino-4-pyrazolecarbonitrile 1 (Acros, 15 g, 0.138 mol), pentyliodide(Acros, 24.45 ml, 0.187 mol) and anhydrous potassium carbonate (Fisher,25.88 g, 0.187 mol) were suspended in 100 mL anhydrous DMF and heated at80° C. under nitrogen overnight. HPLC analysis (Method D) showedstarting material still present. An additional 9 ml (69 mmol) ofpethyliodide and 9.5 g (69 mmol) K₂CO₃ were added to the reaction andheating continued for 5 more hours. The reaction was permitted to cooland the DMF was removed on a rotary evaporator. Water was added (100 mL)and the organics were extracted with dichloromethane (3×100 mL). Thecombined dichloromethane fractions were washed with water (50 mL) andbrine (50 mL) and were dried (magnesium sulfate). Concentration of theorganics afforded orange solid which contained both pentyl isomers andresidual DMF by NMR analysis (27.65 g, greater than theoretical yield).This was carried on crude. HPLC (1 peak, 63%) elutes at 9.5 minutes(Method D). ¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.60 (s, 1H), 6.15(s, 1H), 5.33 (s, 2H), 3.80 (t, J=7, 2H), 1.68 (m, 2H), 1.25 (m, 4H)0.75 (t, J=7, 3H).

Compound 283 and 284 3-Amino-1-pentyl-1H-pyrazole-4-caroboxylic acidamide 5-Amino-1-pentyl-1H-pyrazole-4-carboxylic acid amide

To 4 ml conc. H₂SO₄ at 0° C., was added 1.6 g (8.9 mmol) of the crudemixture (Example 254 and Compound 255) from the above alkylationreaction. The reaction was allowed to stir and warm to room temperature.After 4 h stirring, the entire solid had been dissolved. The thick, acidsolution was added dropwise to stirring, ice cold NH₄OH (aq). Theresulting white precipitate (1.23 g, 70%), as a mixture of the twoisomers, was collected via vacuum filtration, washed with water anddried in vacuo. ¹H NMR (400 MHz, DMSO-d₆) δ 7.82 (s, 1H), 7.58 (s, 1H),7.15 (br s, 2H), 6.65 (br s, 2H), 5.32 (s, 1H), 3.80 (t, J=7 Hz, 2H),1.68 (m, 2H), 1.25 (m, 4H), 0.75 (t, J=7 Hz, 3H).

Compound 285 2-Pentyl-2H-pyrazole[3,4-d]pyrimidine-4,6-diol

In a sealed tube 539 mg (2.75 mmol) of the mixture of isomers (Compound283 and Compound 284) from the above reaction and 1.65 g (27.5 mmol)urea were combined and heated to 180° C. The solids became an off whiteliquid and then returned to solid at approximately 3 h of heating. Thereaction was cooled to 130° C. and 10 ml water added. The aqueoussolution was refluxed overnight, cooled to room temperature in themorning, and filtered. Only the desired isomer was collected as a whitesolid (177 mg, 29%). HPLC (87%) elutes at 7.88 min. (Method B). ¹H NMR(400 MHz, DMSO-d₆) δ 11.35 (s, 1H), 11.65 (s, 1H), 8.35 (s, 1H), 4.10(t, J=7 Hz, 2H), 1.80 (m, 2H), 1.25 (m, 4H), 0.75 (t, J=7 Hz, 3H).

Compound 286 4,6-Dichloro-2-pentyl-2H-pyrazolo[3,4-d]pyrimidine

To 30 ml POCl₃, was added 1.12 g compound 285 prepared as above. Thesolution was refluxed for 5 h and monitored by removing aliquots,quenching them into saturated NaHCO₃ and extracting with ether. ThePOCl₃ was first removed via rotary evaporation and subsequent highvacuum for approximately 1 h. The resulting dark syrup was quenched intostirring ice water and the aqueous solution made basic with 5% NaOH. Thesolution was transferred to a reparatory funnel and extracted with 3×50ml portions of ether. The combined ether was dried over MgSO₄, filteredand evaporated to a white to off white solid (900 mg, 69%). HPLC (99%)elutes at 11.78 min. (Method B). ¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (s,1H), 4.55 (t, J=7 Hz, 2H), 1.90 (m, 2H), 1.28 (m, 4H), 0.9 (t, J=7 Hz,3H).

Example 287 3-(6-Chloro-2-pentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-trifluoromethyl-1,3-dihydro-indol-2-one

To a stirring solution of 5-trifluoromethyloxindole (300 mg, 1.49 mmol)and THF (5 mL), in 50 mL flask at −78° C. was added LDA (1.86 mL, 3.73mmol). After the reaction was stirred for 45 min, a solution of compound286 prepared above (402 mg, 1.55 mmol) in THF (3 mL×2) was added andcontinued to stir for 1 h at −78° C. The reaction was allowed to warm toroom temperature and stirred for additional 2 h. It was quenched withsaturated NH₄Cl (10 mL). The resulting precipitate was filtered, washedwith water, and dried under house vacuum at 50° C. overnight to give 587mg (93%) of the desired product as a light yellow solid: mp=267° C.dec., ¹H NMR (400 MHz, DMSO-d₆) δ 11.45 (br s, 1H), 9.35 (s, 1H), 8.55(s, 1H), 8.35 (m, 1H), 7.25 (s, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 4.25(t, J=7 Hz, 2H), 1.82 (m, 2H), 1.30 (m, 4H), 0.85 (t, J=7 Hz, 3H); MSm/e 424 (M+1), HPLC (99% purity, retention time 13.71 minutes, method B)

General Procedure for Aminations Using Microwave—

In a CEM 10 ml disposable microwave tube equipped with a stir bar, wasplaced 75 mg (0.18 mmol) of the oxidolepyrazolopyrimidine prepared aboveand 2 ml EtOH. To the tube was added 10 eq. of the corresponding amineand the tube heated to 130° C. for 10 min in the microwave reactor. Theresulting solid was filtered and washed with ether and dried in vacuo.If no solid was formed, the EtOH was evaporated and the resulting solidtriturated with ether, filtered and dried in vacuo.

Example 288 3-[6-(2-Amino-ethylamino)-2-pentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-trifluoromethyl-1,3-dihydro-indol-2-one

Yellow solid (37 mg, 46%): mp=192° C. dec., ¹H NMR (400 MHz, DMSO-d₆) δ10.08 (br s, 1H), 9.40 (s, 1H), 7.10 (d, J=5 Hz, 1H), 6.80 (d, J=5 Hz,1H), 4.15 (t, J=7 Hz, 2H), 3.7-3.0 (br m, 4H), 1.82 (m, 2H), 1.25 (m,4H), 0.85 (t, J=7 Hz, 3H); MS m/e 448 (M+1), HPLC (80% purity, retentiontime 9.66 minutes, method B).

Example 2893-[6-(3-Amino-propylamino)-2-pentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-trifluoromethyl-1,3-dihydro-indol-2-one

Yellow solid (15 mg, 16%): mp=235° C. dec., ¹H NMR (400 MHz, DMSO-d₆) δ9.97 (br s, 1H), 9.40 (s, 1H), 8.70 (s, 1H), 7.10 (d, J=5 Hz, 1H), 6.80(d, J=5 Hz, 1H), 4.15 (m, 2H), 3.50 (m, 2H), 2.80 (m, 4H), 1.82 (m, 4H),1.25 (m, 4H), 0.85 (t, J=7 Hz, 3H); MS m/e 462 (M+1), HPLC (80% purity,retention time 9.48 minutes, method B).

Example 2903-[6-(3-Morpholin-4-yl-propylamino)-2-pentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-trifluoromethyl-1,3-dihydro-indol-2-one

Yellow-brown solid (81 mg, 85%): mp=230° C. dec., ¹H NMR (400 MHz,DMSO-d₆) δ 10.30 (s, 1H), 9.40 (s, 1H), 8.70 (s, 1H), 7.10 (d, J=5 Hz,1H), 6.80 (d, J=5 Hz, 1H), 4.15 (m, 2H), 3.30 (m, 2H), 2.80 (m, 4H),1.82 (m, 4H), 1.25 (m, 4H), 0.85 (t, J=7 Hz, 3H); MS m/e 532 (M+1), HPLC(93% purity, retention time 10.10 minutes, method B).

Example 291 3-(6-Chloro-2-pentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

To a stirring solution of 5-cyanoloxindole (166 mg, 1.05 mmol) and THF(2 mL) in 50 mL flask at −78° C. was added LDA (1.31 mL, 2.62 mmol).After the reaction was stirred for 45 min, a solution of compound 286prepared above (290 mg, 1.11 mmol) in THF (1 mL×2) was added andcontinued to stir for 1 h at −78° C. The reaction was allowed to warm toroom temperature and stirred for additional 2 h. It was quenched withsaturated NH₄Cl (10 mL). The resulting precipitate was filtered, washedwith water, and dried under house vacuum at 50° C. overnight to give 115mg (29%) of the desired product as a light yellow solid: mp=254° C.dec., ¹H NMR (400 MHz, DMSO-d₆) δ 10.28 (br s, 1H), 9.45 (s, 1H), 8.55(s, 1H), 7.25 (d, J=7 Hz, 1H), 6.85 (d, J=7 Hz, 1H), 4.25 (t, J=7 Hz,2H), 1.82 (m, 2H), 1.25 (m, 4H), 0.85 (t, J=7 Hz, 3H); MS m/e 381 (M+1),HPLC (97% purity, retention time 11.71 minutes, method B)

General Procedure for Aminations in Radley's Tube—

In a Radley's Tube equipped with a stir bar, was placed 50 mg (0.18mmol) of the 5-cyano oxidolepyrazolopyrimidine prepared above and 2 ml2-methoxyethanol. To the tube was added 10 eq. of the correspondingamine and the tube heated to 130° C. and the reaction followed by LC/MS.When reaction was complete, the solvent was removed via Speedi-Vacovernight. The resulting solid suspended in MeOH, filtered, washed withether and dried in vacuo.

Example 292 2-Oxo-3-{2-pentyl-6-[(pyridin-4-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-2,3-dihydro-1H-indole-5-carbonitrile

Yellow solid (39 mg, 65%): mp=288-290° C. dec., ¹H NMR (400 MHz,DMSO-d₆) δ 11.85 (br, s, 1H), 10.40 (s, 1H), 9.40 (s, 1H), 8.50 (d, J=8Hz, 2H), 8.50 (d, J=8 Hz, 2H), 7.10 (d, J=5 Hz, 1H), 6.80 (d, J=5 Hz,1H), 4.80 (m, 2H), 2.80 (m, 4H), 1.82 (m, 4H), 1.25 (m, 4H), 0.85 (t,J=7 Hz, 3H); MS m/e 453 (M+1), HPLC (98% purity, retention time 7.91minutes, method B).

Example 2933-(6-Allylamino-2-pentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Yellow solid (18 mg, 65%): mp=265° C. dec., ¹H NMR (400 MHz, DMSO-d₆) δ11.55 (br s, 1H), 10.40 (s, 1H), 9.40 (s, 1H), 8.50 (br s, 2H), 8.50 (d,J=8 Hz, 2H), 7.30 (d, J=10 Hz, 1H), 6.80 (d, J=10 Hz, 1H), 6.00 (m, 1H),5.30 (d, J=7 Hz, 1H), 5.15 (d, J=7 Hz, 1H), 4.80 (m, 2H), 2.80 (m, 4H),1.82 (m, 4H), 1.25 (m, 4H), 0.85 (t, J=7 Hz, 3H); MS m/e 402 (M+1), HPLC(99% purity, retention time 9.93 minutes, method B).

Example 294 3-(6-Methylamino-2-pentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Yellow solid (32 mg, 65%): mp=>310° C., ¹H NMR (400 MHz, DMSO-d₆) δ11.75 (s, 1H), 10.40 (s, 1H), 9.40 (s, 1H), 8.75 (s, 1H), 7.30 (d, J=10Hz, 1H), 6.80 (d, J=10 Hz, 1H), 4.80 (m, 2H), 3.0 (s, 3H), 1.82 (m, 4H),1.25 (m, 4H), 0.85 (t, J=7 Hz, 3H); MS m/e 376 (M+1), HPLC (95% purity,retention time 8.81 minutes, method B).

Example 2953-(6-Isopropylamino-2-pentyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Yellow solid (11 mg, 20%): mp=199° C. dec., ¹H NMR (400 MHz, DMSO-d₆) δ10.40 (s, 1H), 9.40 (s, 1H), 8.75 (s, 1H), 7.30 (d, J=10 Hz, 1H), 6.80(d, =10 Hz, 1H), 4.80 (m, 5H), 1.82 (m, 4H), 1.25 (m, 7H), 0.85 (t, J=7Hz, 3H); MS m/e 404 (M+1), HPLC (95% purity, retention time 9.97minutes, method B).

Compound 296 3-Amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester

Methylhydrazine (5.90 g, 128 mmol) and p-anisaldehyde (17.43 g, 128mmol) were refluxed in 100 mL dry benzene employing a Dean-Start trap toremove water. After 24 hours the organics were concentrated and thereaction was reconstituted by the addition of 50 mL anhydrous benzene.Ethyl ethoxymethylenecyanoacetate (21.65 g, 128 mmol) in 50 mL anhydrousbenzene was added dropwise and the mixture was refluxed for one hour.The reaction was concentrated and the remaining organics were trituratedwith ethanol to afford a solid after filtering. To this solid was addedapproximately 100 mL ethanol and 17 mL concentrated hydrochloric acid.The mixture was stirred ½ hour at 80° C. at which point the reactionbecame homogeneous. The reaction was concentrated and the productobtained was triturated with approximately 500 mL boiling ethyl etherfor one hour to remove anisaldehyde. The suspended solid was filteredoff and dissolved in chloroform (approximately 250 mL). The chloroformsolution was washed with saturated sodium bicarbonate solution and wasdried (magnesium sulfate) and concentrated to afford 19.66 g (91%) of apeach solid Compound 296 which was used in succeeding steps withoutpurification.

Compound 297 2-Methyl-2,7-dihydropyrazolo[3,4-d]pyrimidine-4,6-dione

Compound 296 (2 g, 11.8 mmol) was melted at 200° C. with 6 g urea (largeexcess) for two hours. The reaction was permitted to cool to 40° C. and20 mL water was added. The mixture was then boiled for 1 hour andstirred at room temperature overnight. Filtration and drying in vacuoafforded 1.86 g (95%) of a white solid. Compound 297: mp>300° C.; MS(ES⁺ calculated: 166.14; found: 167.24 M+H). HPLC (100% purity,retention time 2.103 minutes—Method A); ¹H NMR (400 MHz, DMSO-d⁶): δ11.34 (br s, 1H), 10.66 (br s, 1H), 8.27 (s, 1H), 3.82 (s, 3H).

Compound 2982-Methyl-6-thioxo-2,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidin-4-one

Compound 296 (2 g, 11.8 mmol) was melted at 200° C. with 6 g thiourea(large excess) for two hours. The reaction was permitted to cool to 40°C. and 50 mL water was added. The mixture was then boiled overnight.Filtration and drying in vacuo afforded 1.06 g (49%) of a white solid.Compound 298: mp>300° C.; MS (ES⁺ calculated: 182.20; found: 183.18M+H). HPLC (100% purity, retention time 5.328 minutes—Method D); ¹H NMR(400 MHz, DMSO-d⁶): δ 13.05 (br s, 1H), 12.86 (br s, 1H), 8.70 (s, 1H),3.88 (s, 3H).

Compound 299 4,6-Dichloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidine

Compound 297 (1.04 g, 5.7 mmol) was refluxed under argon with 50 mLphosphorous oxychloride for 24 hours. Following introduction of apipette for analysis, the suspension became homogeneous afterapproximately an hour. Following homogeneity the reaction was refluxedan additional hour. Excess phosphorus oxychloride was then scrupulouslyremoved in vacuo (high vacuum). Ice was added and the mixtureneutralized to basic by addition of 10N sodium hydroxide solution. Ayellow solid was removed by filtration and dried in vacuo to afford 0.76g (66%). Compound 299: MS (ES⁺ calculated: 203.03; found: 203.19 M+H).HPLC (67% purity—pdt decomposes on hplc column, retention time 6.895minutes—Method A); ¹H NMR (400 MHz, DMSO-d⁶): δ 9.02 (s, 1H), 4.23 (s,3H).

Example 3005-Bromo-3-(6-chloro-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

To 5-bromooxindole (212 mg, 1.0 mmol) in 5 mL anhydrous tetrahydrofuranat −78° C. under argon was added lithium diisopropylamide (1.05 mL of a2.0M solution in THF/hexane, 2.1 mmol) dropwise. The solution wasstirred ten minutes and Compound 299 (202 mg, 1.0 mmol) was added in oneportion. The reaction was permitted to warm to room temperature at whichpoint 2 mL of N-methylpyrrolidinone was added to promote homogeneity.Dissolution occurred and the reaction was stirred for 90 minutes. Thereaction was concentrated and residual solvent was removed vialyophilization. The resulting organics were applied to silica gel andeluted (gradient from 1 to 10% methanol:dichloromethane) to afford 275mg (73%) of an orange solid. Example 300: mp>300° C.; MS (ES⁺calculated: 378.62; found: 380.02 M+H). HPLC (78% purity, retention time11.002 minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 10.47 (br s, 1H),9.26 (br s, 1H), 8.25 (br s, 1H), 7.14 (m, 1H), 6.77 (m, 1H), 4.04 (s,3H), 3.40 (m, 1H).

Example 3013-(6-Allylamino-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-bromo-1,3-dihydro-indol-2-one

Example 300 (30 mg, 0.08 mmol), allylamine (46 mg, 0.90 mmol) andmethoxyethanol (2 mL) were combined and heated in a sealed tube at 130°C. overnight. The reaction was concentrated to afford a solid which wastriturated with 1 mL methanol. Filtration and drying afforded 19 mg(60%) of a yellow solid. Example 301: mp 336-340° C.; MS (ES⁺calculated: 399.25; found: 400.77 M+H). HPLC (96% purity, retention time9.036 minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 11.35 (s, 1H),9.99 (s, 1H), 9.38 (s, 1H), 8.52 (s, 1H), 6.99 (d, J=8 Hz, 1H), 6.65 (d,J=8 Hz, 1H), 6.05 n(m, 1H), 5.31 (d, J=17 Hz, 1H), 5.16 (d, J=10 Hz,1H), 4.15 (m, 2H), 4.01 (m, 1H), 3.92 (s, 3H).

Example 3025-Bromo-3-{2-methyl-6-[(pyridin-4-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydro-indol-2-one

Example 302 was prepared as a gum from the reaction of Example 300 and4-aminomethylpyridine. Yield: 12 mg (33%). Example 302: MS (ES⁺calculated: 450.30; found: 451.79 M+H). HPLC (93% purity, retention time7.220 minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 11.50 (br s, 1H),9.99 (s, 1H), 9.39 (s, 1H), 8.50 (s, 1H), 67.60-7.17 (m, 4H), 6.90 (m,1H), 6.62 (m, 1H), 64.10-3.90 (m, 3H), 3.92 (s, 3H).

Example 303 3-[6-(2-Amino-ethylamino)-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-bromo-1,3-dihydro-indol-2-one

Example 303 was prepared by reacting Example 300 and ethylenediamine.Yield: 19 mg (59%). Example 303: mp 260-2° C.; MS (ES⁺ calculated:402.26; found: 403.79 M+H). HPLC (86% purity, retention time 7.036minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 9.56 (br s, 1H), 9.37(br s, 1H), 8.55 (br s, 1H), 6.79 (m, 1H), 6.57 (m, 1H), 6.43 (br s,1H), 3.88 (s, 3H), 3.60-3.20 (m, 7H).

Example 304 5-Bromo-3-[6-(2-(S)-hydroxypropylamino)-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 304 was prepared from the reaction of Example 300 and(S)-2-hydroxy-1-aminopropane. Yield: 16 mg (48%). Example 304: mp338-40° C.; MS (ES⁺ calculated: 417.27; found: 418.72 M+H). HPLC (97%purity, retention time 7.743 minutes—Method B); ¹H NMR (400 MHz,DMSO-d⁶): δ 10.00 (s, 1H), 9.37 (s, 1H), 8.50 (s, 1H), 7.00 (d, J=8 Hz,1H), 6.67 (d, J=8 Hz, 1H), 3.91 (s, 3H), 3.70-3.20 (m, 4H), 1.22 (m,3H).

Example 3055-Bromo-3-[2-methyl-6-(2-pyridin-3-yl-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 300 (30 mg, 0.08 mmol) and 3-(2′ aminoethyl)pyridine (98 mg,0.80 mmol) in 2 mL ethanol was subjected to reaction at 130° C. in amicrowave for ten minutes. On cooling a mustard brown solid wascollected by filtration. It was washed with ethanol and dried in vacuoto afford 24 mg (65%). Example 305: mp 314-7° C.; MS (ES⁺ calculated:464.33; found: 465.78 M+H). HPLC (96% purity, retention time 7.201minutes—Method B); ¹H NMR (400 MHz, DMSO-d⁶): δ 9.89 (s, 1H), 9.36 (s,1H), 8.60-8.40 (m, 3H), 7.72 (m, 1H), 7.32 (m, 1H), 6.94 (d, J=8 Hz,1H), 6.80 (br s, 1H), 6.64 (d, J=8 Hz, 1H), 3.90 (s, 3H), 3.85-2.80 (m,5H).

Example 3065-Bromo-3-[2-methyl-6-(3-methylamino-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

In a similar fashion to Example 305, BOC protected Example 306 wasprepared from the reaction of Example 300 andN-(3-aminopropyl)-N-methylcarbamic acid-t-butyl ester. The productobtained by filtration from the ethanolic solution was taken up into 4mL 4N hydrochloric acid:dioxane and stirred at room temperature for onehour. The reaction was concentrated and the solid was triturated withethyl ether to afford after filtering 17 mg (46%) of a yellowsolid—isolated as the hydrochloride salt. mp 271-273° C.; MS (ES⁺calculated: 430.31; found: 431.91 M+H). HPLC (92% purity, retention time8.228 minutes—Method D); ¹H NMR (400 MHz, DMSO-d⁶): δ 10.10 (br s, 1H),9.34 (br s, 1H), 8.64 (br s, 1H), 7.27 (br s, 1H), 7.04 (m, 1H), 6.72(m, 1H), 3.95 (s, 3H), 3.38 (d, J=7 Hz, 3H), 3.78-1.80 (m, 9H).

Example 3075-Bromo-3-[6-(3-dimethylamino-propylamino)-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

In a similar manner as for the preparation Example 305, Example 307 wasprepared from the reaction of 300 and N,N-dimethylpropylenediamine inethanol to afford 10 mg (28%) of a yellow solid. Example 307: mp 310-12°C. (dec); MS (ES⁺ calculated: 444.34; found: 445.88 M+H). HPLC (97%purity, retention time 7.155 minutes—Method B); ¹H NMR (400 MHz,DMSO-d⁶): δ 9.93 (s, 1H), 9.37 (s, 1H), 8.54 (s, 1H), 7.00 (br s, 1H),6.97 (d, J=8 Hz, 1H), 6.65 (d, J=8 Hz, 1H), 3.91 (s, 3H), 3.50 (m, 2H),2.47 (m, 2H), 2.23 (s, 6H), 1.81 (m, 2H).

Example 3083-(6-Chloro-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-5-methyl-1,3-dihydroindol-2-one

A solution of 5-methyloxindole (147 mg, 1.0 mmol) and compound 105 (231mg, 1.0 mmol) in 2 mL dry THF and 2 mL dry DMF was cooled to 0° C., anda dispersion of 60% NaH in mineral oil (80 mg, 2.0 mmol) was added.After the hydrogen evolution ceased, the reaction mixture was allowed towarm to rt. The reaction mixture was stirred under N₂ for 2 days. Thedark yellow homogeneous reaction was quenched with sat. NH₄Cl, and ayellow precipitate formed. The precipitate was washed with water, andthe product allowed to air dry. The crude product was then suspended indiethyl ether, and the yellow solid recovered by filtration affording272 mg (80%) of the product: mp 275-80° C. ¹H NMR (400 MHz, TFA-d): δ9.68 (s, 1H), 8.41 (br. s, 1H), 8.09 (d, J=7.8 Hz, 1H), 8.02 (d, J=7.8Hz, 1H), 5.33 (q, J=6.3 Hz, 2H), 3.30 (s, 3H), 2.97 (dq, J=6.3, 7.1 Hz),1.93 (t, J=7.1 Hz).

Example 3093-[6-(2-Dimethylamino-ethylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-methyl-1,3-dihydro-indol-2-one

Using microwave procedure as described previously, the homogeneousreaction mixture was triturated with hexanes to precipitate the productfrom solution. Filtration and ether wash provided the product (15 mg,33% yield) as a yellow solid; mp 255-7° C. ¹H NMR (400 MHz, TFA-d): δ8.83 (s, 1H), 7.66 (s, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.22 (d, J=7.8 Hz,1H), 4.48 (m, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.94 (m, 2H), 3.30 (s, 6H),2.55 (s, 3H), 2.19 (dt, J=7.1, 7.1 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H).

Example 3103-[6-(3-Methoxy-propylamino)-2-propyl-2H-pyrazolo[3,4-d]pryrimidin-4-yl]-5-methyl-1,3-dihydro-indol-2-one

Using microwave procedure as described for Example 309, the yellowprecipitate was recovered by filtration, and the solid washed with waterto provide the product (25 mg, 54%); mp 286-8° C. ¹H NMR (400 MHz,TFA-d): δ 8.75 (s, 1H), 7.59 (br. s, 1H), 7.26 (d, J=7.6 Hz, 1H), 7.16(m, 1H), 4.41 (t, J=7.1 Hz, 2H), 3.95 (t, J=6.6 Hz, 2H), 3.87 (m, 2H),3.65 (s, 3H), 2.48 (s, 3H), 2.33 (m, 2H), 2.11 (dt, J=6.8, 7.4 Hz, 2H),1.12 (t, J=7.3 Hz, 3H).

Compound 312 6,7-Dihydro-5H-cyclopentapyrimidine-2,4-diol

To a 100 mL of flask was added ethyl 2-oxocyclopentanecarboxylate 311(10 mL, 67.2 mmol), urea (6.07 g, 101 mmol), ethanol (20 mL) andconcentrated HCl (1 mL). After the mixture was heated to reflux for 2 h,it was cooled to room temp. The ethanol was decanted and remain whitecrystalline was heated to reflux in 5% NaOH solution (25 mL) for 30 min.The reaction was cooled to room temp and the precipitate was collectedby filtration. It was washed with water and dried to give 6.77 g (66%)of the title compound 312. Compound 312: ¹H NMR (400 MHz, DMSO-d₆) δ11.03 (s, 1H), 10.72 (s, 1H), 2.63 (m, 2H), 2.44 (m, 2H), 1.98-1.91 (m,2H); MS (m/e) 153 (M+1).

Compound 313 2,4-Dichloro-6,7-dihyro-5H-cyclopentapyrimidine

To a 100 mL flask was added compound 312 (3.00 g, 19.7 mmol) and POCl₃(15 mL). The reaction mixture was heated to reflux for 5 h. After cooledto room temp, the reaction was concentrated in vacuo. The gummy residuewas quenched with ice-water and the resulted precipitation was collectedby filtration. It was washed with water and dried to give 3.10 g (83%)of the title compound 313. Compound 313: ¹H NMR (400 MHz, DMSO-d₆) δ3.03 (m, 2H), 2.93 (m, 2H), 2.17-2.09 (m, 2H); MS (m/e) 190 (M+1).

Example 3145-Bromo-3-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-1,3-dihydro-indol-2-one

To a stirring mixture of NaH (480 mg, 12.0 mmol) in THF (20 mL) at 0° C.was added 5-bromooxindole (1.00 g, 4.72 mmol) in portion. Additional THF(5 mL×3) was used to make sure all the oxindole was added into thereaction flask. After stirred for 50 min, a solution of compound 313(892 mg, 4.72 mmol) in THF (5 mL×3) was added. The reaction wascontinued stir for 1 h at 0° C. and 2.5 h at room temp. A saturatedNH₄Cl solution (50 mL) was added into the reaction and the mixture wasextracted with EtOAc (50 mL×3). The combined organic extracts was washedwith brine and concentrated. The residue was triturated with MeOH anddried to give 1.27 g (74%) of the title Example 314. Example 314: ¹H NMR(400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 7.43 (m, 1H), 7.27 (s, 1H), 6.87 (m,1H), 5.11 (s, 1H), 3.02-2.76 (m, 4H), 2.13-2.03 (m, 2H); MS (m/e) 365(M+1), 366 (M+2).

Example 3153-(2-Chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-5-fluoro-1,3-dihydro-indol-2-one

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.74 (s, 1H), 7.11-6.89(m, 3H), 5.09 (s, 1H), 3.00-2.73 (m, 4H), 2.12-2.03 (m, 2H); MS (m/e)304 (M+1).

Example 3165-Chloro-3-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-1,3-dihydro-inodol-2-one

Experimental data: ¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 7.30 (m,1H), 7.16 (m, 1H), 6.92 (m, 1H), 5.10 (s, 1H), 3.02-2.76 (m, 4H), 2.10(m, 2H); MS (m/e) 320 (M+1).

Example 3173-(2-Chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

To mixture of 5-cyanooxindole (1.00 g, 6.32 mmol) and NaH (650 mg, 16.3mmol) was added THF (20 mL). After the reaction mixture was stirred for45 min at rt, a solution of 313 (1.20 g, 6.32 mmol) in THF (10 mL) wasadded. The reaction was heated to reflux for 2 h, and was cooled to roomtemp. Water (30 mL) was slowly added to the reaction, and was acidifiedto pH ˜3 with concentrated HCl. The resulting precipitate was collectedby filtration. It was washed with water, MeOH, and dried to give 1.31 g(67%) of the desired Example 317. ¹HNMR (400 MHz, DMSO-d₆) δ 11.18 (s,1H), 7.73 (m, 1H), 7.57 (s. 1H), 7.06 (m, 1H), 5.17 (s, 1H), 3.01 (m,2H), 2.83 (m, 2H), 2.10 (m, 2H); MS (m/e) 311 (M+1).

The following Examples 318-354 in Table 5 were prepared according toprocedures disclosed herein including using methods generally known toone skilled in the art.

TABLE 5

Example R² X 318 F

319 F

320 F

321 F

322 F

323 Cl

324 Cl

325 Cl

326 Cl

327 Cl

328 Cl

329 Cl

330 Cl

331 Br

332 Br

333 Br

334 Br

335 Br

336 Br

337 Br

338 Br

339 Br

340 CN

341 CN

342 CN

343 CN

344 CN

345 CN

346 CN

347 CN

348 CN

349 CN

350 CN

351 CN

352 CN

353 CN

354 CN

Example 3185-Fluoro-3-[2-(2-morpholin-4-ylethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.41 (s, 1H), 10.54 (s, 1H), 7.99 (s, 1H),7.38 (m, 1H), 6.80 (m, 1H), 6.65 (m, 1H), 3.58 (m, 4H), 3.43 (m, 2H),3.21 (m, 2H), 2.69 (m, 2H), 2.50 (m, 2H), 2.42 (m, 4H), 2.02 (m, 2H); MS(m/e) 398 (M+1).

Example 3193-[2-(2-Ethoxy-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-5-fluoro-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.41 (s, 1H), 10.53 (s, 1H), 8.16 (s, 1H),7.38 (m, 1H), 6.79 (m, 1H), 6.66 (m, 1H), 3.53 (m, 1H), 3.47 (m, 4H),3.21 (m, 2H), 2.69 (m, 2H), 2.02 (m, 2H), 1.11 (m, 3H); MS (m/e) 357(M+1).

Example 3205-Fluoro-3-{2-[(pyridin-4-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.63 (s, 1H), 10.59 (s, 1H), 8.70 (s, 1H),8.51 (m, 2H), 7.39 (m, 1H), 7.33 (m, 2H), 6.80 (m, 1H), 6.66 (m, 1H),4.57 (m, 2H), 3.22 (m, 2H), 2.67 (m, 2H), 2.01 (m, 2H); MS (m/e) 376(M+1).

Example 3215-Fluoro-3-{2-[(pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.60 (s, 1H), 10.56 (s, 1H), 8.66 (m, 1H),8.59 (s, 1H), 8.47 (m, 1H), 7.76 (m, 1H), 7.38 (m, 2H), 6.79 (m, 1H),6.66 (m, 1H), 4.56 (d, 2H), 3.22 (m, 2H), 2.70 (m, 2H), 2.02 (m, 2H); MS(m/e) 376 (M+1).

Example 3225-Fluoro-3-{2-[(pyridin-2-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.58 (s, 1H), 10.55 (s, 1H), 8.67 (s, 1H),8.52 (m, 1H), 7.76 (m, 1H), 7.37 (m, 2H), 7.27 (m, 1H), 6.80 (m, 1H),6.66 (m, 1H), 4.65 (m, 2H), 3.21 (m, 2H), 2.67 (m, 2H), 2.01 (m, 2H); MS(m/e/) 376 (M+1).

Example 3235-Chloro-3-[2-(2-dimethylamino-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s, 1H), 7.97 (s, 1H), 7.60 (m, 1H),6.84 (m, 2H), 3.41 (m, 2H), 3.18 (m, 2H), 2.69 (m, 2H), 2.45 (m, 2H),2.20 (s, 6H), 2.02 (m, 2H); MS (m/e) 372 (M+1).

Example 3245-Chloro-3-[2-(2-morpholin-4-yl-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.33 (s, 1H), 10.65 (s, 1H), 8.02 (s, 1H),7.59 (s, 1H), 6.85 (m, 2H), 3.57 (m, 4H), 3.43 (m, 2H), 3.19 (m, 2H),2.69 (m, 2H), 2.50 (m, 2H), 2.43 (m, 4H), 2.03 (m, 2H); MS (m/e) 414(M+1).

Example 3255-Chloro-3-[2-(2-ethoxy-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.29 (s, 1H), 10.63 (s, 1H), 8.19 (s, 1H),7.59 (s, 1H), 6.85 (m, 2H), 3.53 (m, 2H), 3.46 (m, 4H), 3.19 (m, 2H),2.70 (m, 2H), 2.03 (m, 2H), 1.11 (m, 3H); MS (m/e) 373 (M+1).

Example 3265-Chloro-3-{2-[(pyridin-4-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.54 (s, 1H), 10.70 (s, 1H), 8.73 (s, 1H),8.51 (m, 2H), 7.61 (s, 1H), 7.34 (m, 2H), 6.85 (m, 2H), 4.57 (m, 2H),3.20 (m, 2H), 2.68 (m, 2H), 2.02 (m, 2H); MS (m/e) 392 (M+1).

Example 3275-Chloro-3-{2-[(pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.49 (s, 1H), 10.69 (s, 1H), 8.70 (s, 1H),8.59 (m, 1H), 8.47 (m, 1H), 7.76 (m, 1H), 7.60 (s, 1H), 7.37 (m, 1H),6.85 (m, 2H), 4.56 (m, 2H), 3.20 (m, 2H), 2.70 (m, 2H), 2.03 (m, 2H); MS(m/e) 392 (M+1).

Example 3285-Chloro-3-{2-[(6-chloro-pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.52 (s, 1H), 10.71 (s, 1H), 8.68 (m, 1H),8.42 (m, 1H), 7.84 (m, 1H), 7.60 (s, 1H), 7.49 (m, 1H), 6.85 (m, 2H),4.55 (m, 2H), 3.20 (m, 2H), 2.70 (m, 2H), 2.03 (m, 2H); MS (m/e) 426(M+1).

Example 3295-Chloro-3-{2-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.57 (s, 1H), 10.72 (s, 1H), 8.78 (s, 2H),8.04 (m, 1H), 7.88 (m, 1H), 7.61 (m, 1H), 6.86 (m, 2H), 6.67 (m, 2H),3.20 (m, 2H), 2.70 (m, 2H), 2.02 (m, 2H); MS (m/e) 460 (M+1).

Example 3305-Chloro-3-{2-[(pyridin-2-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.46 (s, 1H), 10.66 (s, 1H), 8.70 (s, 1H),8.52 (m, 1H), 7.76 (m, 1H), 7.59 (s, 1H), 7.36 (m, 1H), 7.26 (m, 1H),6.85 (m, 2H), 4.64 (m, 2H), 3.19 (m, 2H), 2.67 (m, 2H), 2.02 (m, 2H); MS(m/e) 392 (M+1).

Example 3315-Bromo-3-[2-(3-morpholin-4-yl-propylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.35 (s, 1H), 10.65 (s, 1H), 8.12 (s, 1H),7.74 (s, 1H), 6.98 (m, 1H), 6.79 (m, 1H), 3.56 (m, 4H), 3.35 (m, 2H),3.18 (m, 2H), 2.69 (m, 2H), 2.36 (m, 6H), 2.03 (m, 2H), 1.72 (m, 2H); MS(m/e) 472 (M).

Example 3325-Bromo-3-[2-(2-morpholin-4-yl-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.30 (s, 1H), 10.66 (s, 1H), 8.02 (s, 1H),7.73 (s, 1H), 6.98 (m, 1H), 6.81 (m, 1H), 3.57 (m, 4H), 3.43 (m, 2H),3.17 (m, 2H), 2.70 (m, 2H), 2.50 (m, 2H), 2.43 (m, 4H), 2.03 (m, 2H); MS(m/e) 458 (M).

Example 3335-Bromo-3-[2-(2-propoxy-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.26 (s, 1H), 10.64 (s, 1H), 8.18 (s, 1H),7.72 (s, 1H), 6.98 (m, 1H), 6.80 (m, 1H), 3.52 (m, 2H), 3.48 (m, 2H),3.37 (m, 2H), 3.17 (m, 2H), 2.70 (m, 2H), 2.03 (m, 2H), 1.50 (m, 2H),0.85 (m, 3H); MS (m/e) 431 (M).

Example 3345-Bromo-3-[2-(2-ethoxy-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.24 (s, 1H), 10.65 (s, 1H), 8.20 (s, 1H),7.72 (s, 1H), 6.98 (m, 1H), 6.80 (m, 1H), 3.52 (m, 2H), 3.46 (m, 4H),3.17 (m, 2H), 2.70 (m, 2H), 2.03 (m, 2H), 1.11 (m, 3H); MS (m/e) 417(M).

Example 3355-Bromo-3-[2-(3-dimethylamino-propylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one

H NMR (400 MHz, DMSO-d₆) δ 15.23 (s, 1H), 10.60 (s, 1H), 8.06 (s, 1H),7.75 (s, 1H), 6.96 (m, 1H), 6.78 (m, 1H), 3.32 (m, 2H), 3.17 (m, 2H),2.69 (m, 2H), 2.30 (m, 2H), 2.14 (s, 6H), 2.02 (m, 2H), 1.70 (m, 2H); MS(m/e) 430 (M).

Example 3365-Bromo-3-{2-[(pyridin-4-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.55 (s, 1H), 10.72 (s, 1H), 8.74 (m, 1H),8.51 (m, 2H), 7.74 (s, 1H), 7.34 (m, 2H), 7.00 (m, 1H), 6.80 (m, 1H),4.57 (m, 2H), 3.18 (m, 2H), 2.68 (m, 2H), 2.02 (m, 2H); MS (m/e) 436(M).

Example 3375-Bromo-3-{2-[(pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.44 (s, 1H), 10.67 (s, 1H), 8.70 (s, 1H),8.52 (m, 1H), 7.76 (m, 1H), 7.73 (s, 1H), 7.36 (m, 1H), 7.27 (m, 1H),6.99 (m, 1H), 6.80 (m, 1H), 4.64 (m, 2H), 3.18 (m, 2H), 2.67 (m, 2H),2.02 (m, 2H); MS (m/e) 436 (M).

Example 3385-Bromo-3-{2-[(6-chloro-pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.49 (s, 1H), 10.71 (s, 1H), 8.68 (m, 1H),8.41 (m, 1H), 7.84 (m, 1H), 7.74 (s, 1H), 7.49 (m, 1H), 6.99 (m, 1H),6.80 (m, 1H), 4.55 (m, 2H), 3.18 (m, 2H), 2.70 (m, 2H), 2.03 (m, 2H); MS(m/e) 470 (M).

Example 3395-Bromo-3-{2-[(pyridin-2-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one

¹H NMR (400 MHz, DMSO-d₆) δ 15.46 (s, 1H), 10.68 (s, 1H), 8.70 (s, 1H),8.59 (m, 1H), 8.46 (m, 1H), 7.76 (m, 2H), 7.36 (m, 1H), 6.98 (m, 1H),6.79 (m, 1H), 4.56 (m, 2H), 3.18 (m, 2H), 2.70 (m, 2H), 2.03 (m, 2H); MS(m/e) 436 (M).

Example 3403-[2-(3-Morpholin-4-yl-propylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 15.13 (s, 1H), 11.02 (s, 1H), 8.21 (s, 1H),7.89 (s, 1H), 7.25 (m, 1H), 6.97 (m, 1H), 3.57 (m, 4H), 3.35 (m, 2H),3.22 (m, 2H), 2.71 (m, 2H), 2.36 (m, 6H), 2.04 (m, 2H), 1.73 (m, 2H); MS(m/e) 419 (M+1).

Example 3413-[2-(2-Morpholin-4-yl-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 15.04 (s, 1H), 11.03 (s, 1H), 8.12 (s, 1H),7.87 (s, 1H), 7.25 (m, 1H), 6.97 (m, 1H), 3.57 (m, 4H), 3.45 (m, 2H),3.21 (m, 2H), 2.72 (m, 2H), 2.51 (m, 2H), 2.43 (m, 4H), 2.04 (m, 2H); MS(m/e) 405 (M+1).

Example 3423-[2-(3-Dimethylamino-propylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 14.90 (s, 1H), 10.89 (s, 1H), 7.92 (s, 1H),7.22 (m, 1H), 6.95 (m, 1H), 3.34 (m, 2H), 3.20 (m, 3H), 2.71 (m, 2H),2.35 (m, 2H), 2.18 (s, 6H), 2.02 (m, 2H), 1.72 (m, 2H); MS (m/e) 377(M+1).

Example 3432-Oxo-3-[2-(2-propoxy-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 15.02 (s, 1H), 11.01 (s, 1H), 8.28 (s, 1H),7.87 (s, 1H), 7.26 (m, 1H), 6.98 (m, 1H), 3.53 (m, 2H), 3.49 (m, 2H),3.37 (m, 2H), 3.22 (m, 2H), 2.72 (m, 2H), 2.04 (m, 2H), 1.50 (m, 2H),0.85 (m, 3H); MS (m/e) 378 (M+1).

Example 3443-[2-(2-Ethoxy-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 14.99 (s, 1H), 11.01 (s, 1H), 8.30 (s, 1H),7.87 (s, 1H), 7.26 (m, 1H), 6.98 (m, 1H), 3.53 (m, 2H), 3.47 (m, 4H),3.22 (m, 2H), 2.72 (m, 2H), 2.05 (m, 2H), 1.12 (m, 3H); MS (m/e) 364(M+1).

Example 3452-Oxo-3-[2-(2-pyridin-4-yl-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.48 (m, 2H), 8.33 (s, 1H),7.89 (s, 1H), 7.32 (m, 2H), 7.26 (m, 1H), 6.98 (m, 1H), 3.60 (m, 2H),3.23 (m, 2H), 2.92 (m, 2H), 2.72 (m, 2H), 2.04 (m, 2H); MS (m/e) 397(M+1).

Example 3462-Oxo-3-[2-(2-pyridin-2-yl-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 8.50 (m, 1H), 8.31 (s, 1H),7.88 (s, 1H), 7.72 (m, 1H), 7.33 (m, 1H), 7.24 (m, 2H), 6.99 (m, 1H),3.70 (m, 2H), 3.23 (m, 2H), 3.05 (m, 2H), 2.72 (m, 2H), 2.05 (m, 2H); MS(m/e) 397 (M+1).

Example 3472-Oxo-3-{2-[(pyridin-4-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 15.30 (s, 1H), 11.09 (s, 1H), 8.83 (s, 1H),8.51 (m, 2H), 7.89 (s, 1H), 7.34 (m, 2H), 7.27 (m, 1H), 6.99 (m, 1H),4.59 (m, 2H), 3.23 (m, 2H), 2.70 (m, 2H), 2.04 (m, 2H); MS (m/e) 383(M+1).

Example 3482-Oxo-3-{2-[(pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 15.26 (s, 1H), 11.06 (s, 1H), 8.79 (s, 1H),8.59 (m, 1H), 8.47 (m, 1H), 7.90 (s, 1H), 7.77 (m, 1H), 7.37 (m, 1H),7.26 (m, 1H), 6.97 (m, 1H), 4.58 (m, 2H), 3.22 (m, 2H), 2.72 (m, 2H),2.04 (m, 2H); MS (m/e) 383 (M+1).

Example 3492-Oxo-3-{2-[(pyridin-2-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 15.17 (s, 1H), 11.05 (s, 1H), 8.80 (s, 1H),8.52 (m, 1H), 7.88 (s, 1H), 7.76 (m, 1H), 7.37 (m, 1H), 7.28 (m, 2H),6.98 (m, 1H), 4.65 (m, 2H), 3.22 (m, 2H), 2.70 (m, 2H), 2.03 (m, 2H); MS(m/e) 383 (M+1).

Example 3502-Oxo-3-[2-(pyridin-3-ylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H), 9.27 (s, 1H), 9.09 (s, 1H),8.12 (s, 1H), 7.86 (m, 2H), 7.15 (m, 1H), 6.99 (m, 1H), 6.86 (m, 2H),3.20 (m, 2H), 2.93 (m, 2H), 2.07 (m, 2H); MS (m/e) 369 (M+1).

Example 3513-[2-(6-Fluoro-pyridin-3-ylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 15.40 (s, 1H), 11.10 (s, 1H), 9.68 (s, 1H),8.39 (s, 1H), 7.96 (s, 1H), 7.73 (m, 1H), 7.57 (s, 1H), 7.06 (m, 2H),2.89 (m, 2H), 2.80 (m, 2H), 2.07 (m, 2H); MS (m/e) 387 (M+1).

Example 3523-[2-(6-Methoxy-pyridin-3-ylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 15.39 (s, 1H), 11.12 (s, 1H), 10.15 (s, 1H),8.33 (m, 1H), 7.93 (s, 1H), 7.88 (m, 1H), 7.56 (s, 1H), 7.28 (m, 1H),6.85 (m, 1H), 3.86 (s, 3H), 3.26 (m, 2H), 2.76 (m, 2H), 2.08 (m, 2H); MS(m/e) 399 (M+1).

Example 3533-[2-(4-Methyl-piperazin-1-yl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.97 (s, 1H), 7.26 (s, 1H),7.01 (s, 1H), 3.71 (s, 3H), 3.29 (m, 4H), 2.74 (m, 2H), 2.50 (m, 2H),2.26 (m, 4H), 2.05 (m, 2H); MS (m/e) 375 (M+1).

Example 3542-Oxo-3-(2-piperazin-1-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-2,3-dihydro-1H-indole-5-carbonitrile

¹H NMR (400 MHz, DMSO-d₆) δ 10.22 (s, 1H), 7.98 (s, 1H), 7.03 (m, 1H),6.83 (m, 1H), 3.80 (m, 4H), 3.14 (m, 2H), 3.01 (m, 4H), 2.67 (m, 2H),1.94 (m, 2H); MS (m/e) 361 (M+1).

Compound 355 Pyrido[2,3-d]pyrimidine-2,4-diol

A mixture of 2-aminonicotinic acid (5.00 g, 36.2 mmol) and urea (10.9 g,181 mmol) in a 100 mL flask was heated to 195° C. for 1.5 h. After thereaction was cooled to room temp, NaOH (1.45 g, 36.2 mmol) and water (50mL) was added. The mixture was heated to reflux for 1 h and cooled toroom temp. The reaction solution was acidified to pH 4, the resultingprecipitate was collected by filtration. It was washed with water anddried to give 4.49 g (76%) the title Compound 355. ¹H NMR (400 MHz,DMSO-d₆) δ 11.66 (s, 1H), 11.45 (s, 1H), 8.60 (m, 1H), 8.26 (m, 1H),7.24 (m, 1H).

Compound 356 2,4-Dichloro-pyrido[2,3-d]pyrimidine

To a 100 mL flask was added Compound 355 (500 mg, 3.06 mmol),N,N-diethylaniline (1 mL), and POCl₃ (10 mL). The reaction mixture washeated to reflux for 5.5 h. After cooled to room temp, the reaction wasconcentrated in vacuo. The residue was quenched with ice-water (50 mL)and was immediately extracted with CHCl₃ (50 mL×3). The combined organicextracts was washed with water (50 mL), dried (MgSO₄), filtered andconcentrated to give crude the title Compound 356. The material was usedfor next step without purification.

Example 3575-Bromo-3-(2-chloro-pyrido[2,3-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

To a stirring mixture of NaH (260 mg, 6.50 mmol) in THF (20 mL) at 0° C.was added 5-bromooxindole (551 g, 2.60 mmol) in portion. Additional THF(5 mL×2) was used to make sure all the oxindole was added into thereaction flask. After stirred for 1 h, a solution of crude compound 356in THF (5 mL×3) was added. The reaction was continued stir for 1 h at 0°C. and 24 h at room temp. A saturated NH₄Cl solution (30 mL) was addedinto the reaction and the resulted red precipitate was collected byfiltration. It was dried to give 361 mg (37%) the title Example 357. ¹HNMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 10.11 (s, 1H), 8.61 (m, 1H),8.50 (s, 1H), 7.47 (m, 1H), 7.18 (m, 1H), 6.73 (m, 1H); MS (m/e) 376(M+1).

Example 3585-Bromo-3-[6-(2-(R)-hydroxy-propylamino)-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydroindol-2-one

Example 300 (30 mg, 0.079 mmol) and (R)-(−)-1-amino-2-propanol (62 μL,0.79 mmol) were heated in 1 mL EtOH at 130° C. in microwave for 10 min.Upon cooling, the product precipitated in the reaction tube. Theresulting solid was filtered and pumped dry to afford 22 mg (67%) of abright yellow solid. mp 298-301° C.; MS (ES⁺ calculated: 417.27; found:417.61, 418.73 M+H). HPLC (91%) purity, retention time 2.484minutes—Method C); ¹H NMR (400 MHz, TFA) δ 8.75 (s, 1H), 8.4 (s, 1H),7.55 (br d, 1H), 7.1 (br s, 1H), 4.5 (m, 1H), 4.2 (s, 2H), 3.8 (m, 1H),3.7 (m, 1H), 1.6 (d, 2H).

Example 3595-Bromo-3-[6-(2-dimethylamino-ethylamino)-2-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 300 (30 mg, 0.079 mmol) and N,N-dimethylaminoethylamine (69 mg,0.79 mmol) were heated in 1 mL EtOH at 130° C. in microwave for 10 min.Upon cooling, the product precipitated in the reaction tube. Theresulting solid was filtered and pumped dry to afford 14 mg (41%) of abrown solid. mp 279-289° C.; MS (ES⁺ calculated: 430.31; found: 430.67,431.82 M+H). HPLC (88%) purity, retention time 2.375 minutes—Method C);¹H NMR (400 MHz, TFA) δ 8.81 (s, 1H), 7.96 (s, 1H), 7.62 (d, J=9 Hz, 1H)7.24 (d, J=8 Hz, 1H), 4.37 (m, 2H), 4.31 (s, 3H), 3.94 (m, 3H), 3.30 (s,6H), 3.26 (s, 1H).

Example 3605-Bromo-3-[2-methyl-6-(2-methylamino-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-onehydrochloride salt

Example 300 (40 mg, 0.106 mmol) and N-(3-aminoethyl)-N-methyl carbamicacid t-butyl ester (184 mg, 1.06 mmol) were heated in 1 mL EtOH at 130°C. in microwave for 10 min. Upon cooling, the product precipitated inthe reaction tube. The resulting solid was filtered and pumped drybefore stirring in 5 mL of 4N HCl/dioxane for 1 h at RT. The reactionmixture was pumped dry, triturated in ether and filtered to afford 19 mg(40%) of a yellow solid. mp 269-272° C.; MS (ES⁺ calculated: 416.28;found: 416.58, 417.79 M+H). HPLC (88%) purity, retention time 2.357minutes—Method C); ¹H NMR (400 MHz, TFA) δ 8.74 (s, 1H), 7.89 (s, 1H),7.54 (d, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 4.32 (m, 1H), 4.25 (s, 4H),4.07 (m, 1H), 3.85 (m, 3H), 3.11 (br s, 2H), 3.07 (s, 1H).

Example 3615-Bromo-3-{2-propyl-6-[((S)-1-pyrrolidin-2-ylmethyl)-amino]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}-1,3-dihydro-indol-2-one

Example 188 (30 mg, 0.0737 mmol) and (S)-(+)-2-(aminomethyl)pyrrolidine(79 μL, 0.737 mmol) were heated in 1 mL EtOH at 130° C. in microwave for10 min. Upon cooling, the product precipitated in the reaction tube. Theresulting solid was filtered and pumped dry to afford 15 mg (43%) of ayellow solid. mp 286-293° C.; MS (ES⁺ calculated: 470.38; found: 470.65,471.81 M+H). HPLC (97%) purity, retention time 3.66 minutes—Method C);¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (s, 1H), 9.39 (s, 1H), 8.57 (s, 1H),7.85 (br s, 4H), 6.80 (d, J=8 Hz, 1H), 6.59 (d, J=8 Hz, 1H), 4.18 (m,1H), 4.09 (t, J=7 Hz, 2H), 3.86 (m, 1H), 3.74 (m, 1H), 3.07 (d, J=12 Hz,1H), 2.94 (m, 1H), 2.14 (m, 1H), 2.01 (m, 1H), 1.98 (m, 1H), 1.85 (m,3H), 0.85 (t, J=8 Hz, 3H).

Example 3625-Bromo-3-[2-propyl-64(S)-pyrrolidin-3-ylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 188 (40 mg, 0.0983 mmol) and (S)-(−)-3-aminopyrrolidine (87 μL,0.983 mmol) were heated in 1 mL EtOH at 130° C. in microwave for 10 min.Upon cooling, the product precipitated in the reaction tube. Theresulting solid was filtered and pumped dry to afford 44 mg (98%) of ayellow solid. mp 315-320° C.; MS (ES⁺ calculated: 456.35; found: 456.63,457.79 M+H). HPLC (99%) purity, retention time 3.40 minutes—Method C);¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 9.40 (s, 1H), 8.55 (s, 1H),6.86 (d, J=8 Hz, 1H), 6.61 (d, J=8 Hz, 1H), 5.9 (br s, 2H), 4.11 (t, J=7Hz, 2H), 3.77 (br s, 2H), 3.70 (br s, 2H), 3.43 (m, 2H), 2.18 (m, 1H),1.86 (m, 4H), 1.07 (m, 2H), 0.85 (t, J=7 Hz, 3H).

Example 363 5-Bromo-3-[2-propyl-64(R)-pyrrolidin-3-ylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 188 (45 mg, 0.11 mmol) and (R)-(+)-3-aminopyrrolidine (96 μL,1.1 mmol) were heated in 1 mL EtOH at 130° C. in microwave for 10 min.Upon cooling, the product precipitated in the reaction tube. Theresulting solid was filtered and pumped dry to afford 46 mg (92%) of ayellow solid. mp 314-320° C.; MS (ES⁺ calculated: 456.35; found: 456.63,457.78 M+H). HPLC (96%) purity, retention time 3.389 minutes—Method C);¹H NMR (400 MHz, DMSO-d₆) δ 9.71 (s, 1H), 9.40 (s, 1H), 8.55 (s, 1H),6.87 (d, J=8 Hz, 1H), 6.62 (d, J=8 Hz, 1H), 4.11 (t, J=7 Hz, 2H), 3.77(br s, 2H), 3.70 (br s, 2H), 3.43 (m, 2H), 2.18 (m, 1H), 1.86 (m, 4H),0.85 (t, J=7 Hz, 3H).

Example 3645-Bromo-3-[6-((S)-2,3-dihydroxy-propylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 188 (40 mg, 0.0983 mmol) and (S)-(−)-3-amino-1,2-propanediol (89mg, 0.983 mmol) were heated in 1 mL EtOH at 130° C. in microwave for 10min. Upon cooling, the product precipitated in the reaction tube. Theresulting solid was filtered and pumped dry to afford 28 mg (62%) of ayellow solid. mp 295-297° C.; MS (ES⁺ calculated: 461.32; found: 461.64,462.71 M+H). HPLC (93%) purity, retention time 3.517 minutes—Method C);¹HNMR (400 MHz, TFA) δ 8.74 (s, 1H), 7.90 (s, 1H), 7.53 (d, J=8 Hz, 1H),7.17 (d, J=8 Hz, 1H), 4.52 (m, 1H), 4.44 (m, 2H), 4.18 (m, 2H), 3.99 (m,2H), 2.12 (q, J=7 Hz, 2H), 1.36 (m, 1H), 1.12 (t, J=7 Hz, 3H).

Example 365 5-Bromo-3-[6-(2-methylamino-ethylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one hydrochloride salt

Example 188 (50 mg, 0.123 mmol) and N-(3-aminoethyl)-N-methyl carbamicacid t-butyl ester (214 mg, 1.23 mmol) were heated in 1 mL EtOH at 130°C. in microwave for 10 min. Upon cooling, the product precipitated inthe reaction tube. The resulting solid was filtered and pumped drybefore stirring in 5 mL of 4N HCl/dioxane for 1 h at r.t. The reactionmixture was pumped dry, triturated in ether and filtered to afford 38 mg(65%) of a yellow solid. mp 269-271° C.; MS (ES⁺ calculated: 444.34;found: 444.63, 445.75 M+H). HPLC (95%) purity, retention time 3.937minutes—Method C); ¹H NMR (400 MHz, TFA) δ 8.73 (s, 1H), 7.89 (s, 1H),7.54 (d, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 4.4 (m, 2H), 4.31 (br s,2H), 4.07 (m, 1H), 3.85 (m, 3H), 3.10 (br s, 2H), 2.12 (m, 2H), 1.13 (t,J=7 Hz, 3H).

Example 3665-Bromo-3-(2-propyl-6-{[(R)-1-(tetrahydro-furan-2-yl)methyl]-amino}-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Example 188 (40 mg, 0.0983 mmol) and (R)-(−)-tetrahydrofurfurylamine(101 μL, 0.983 mmol) were heated in 1 mL EtOH at 130° C. in microwavefor 10 min. Upon cooling, the product precipitated in the reaction tube.The resulting solid was filtered and pumped dry to afford 26 mg (56%) ofa yellow solid. mp 309-312° C.; MS (ES⁺ calculated: 471.36; found:471.66, 472.78 M+H). HPLC (98%) purity, retention time 11.134minutes—Method B); ¹H NMR (400 MHz, TFA) δ 8.74 (s, 1H), 7.90 (s, 1H),7.53 (d, J=8, 1H), 7.19 (br d, 1H), 4.62 (br s, 1H), 4.44 (t, J=7, 2H),4.19 (t, J=7, 2H), 3.91 (br d, 1H), 3.77 (m, 1H), 2.44 (m, 1H), 2.4-1.9(m, 5H), 1.13 (t, J=7, 3H).

Example 3675-Bromo-3-(2-propyl-6-{[(S)-1-(tetrahydro-furan-2-yl)methyl]-amino}-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Example 188 (40 mg, 0.0983 mmol) and (S)-(+)-tetrahydrofurfurylamine(101 μL, 0.983 mmol) were heated in 1 mL EtOH at 130° C. in microwavefor 10 min. Upon cooling, the product precipitated in the reaction tube.The resulting solid was filtered and pumped dry to afford 32 mg (69%) ofa yellow solid. mp 309-312° C.; MS (ES⁺ calculated: 471.36; found:471.63, 472.78 M+H). HPLC (98%) purity, retention time 4.738minutes—Method C); ¹H NMR (400 MHz, TFA) δ 8.74 (s, 1H), 7.90 (s, 1H),7.53 (d, J=8, 1H), 7.19 (br d, 1H), 4.62 (br s, 1H), 4.44 (t, J=7, 2H),4.19 (t, J=7, 2H), 3.91 (br d, 1H), 3.77 (m, 1H), 2.44 (m, 1H), 2.4-1.9(m, 5H), 1.13 (t, J=7, 3H).

Example 3685-Bromo-3-[6-((R)-2,3-dihydroxy-propylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 188 (40 mg, 0.0983 mmol) and (R)-(+)-3-amino-1,2-propanediol (89mg, 0.983 mmol) were heated in 1 mL EtOH at 130° C. in microwave for 10min. Upon cooling, the product precipitated in the reaction tube. Theresulting solid was filtered and pumped dry to afford 32 mg (71%) of ayellow solid. mp 293-296° C.; MS (ES⁺ calculated: 461.32; found: 461.60,462.75 M+H). HPLC (93%) purity, retention time 9.155 minutes—Method B);¹H NMR (400 MHz, TFA) δ 8.74 (s, 1H), 7.90 (s, 1H), 7.53 (d, J=8 Hz,1H), 7.17 (d, J=8 Hz, 1H), 4.52 (m, 1H), 4.44 (m, 2H), 4.18 (m, 2H),3.99 (m, 2H), 2.12 (q, J=7 Hz, 2H), 1.36 (m, 1H), 1.12 (t, J=7 Hz, 3H).

Example 3693-[6-(2-(R)-Amino-propylamino)-2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-5-bromo-1,3-dihydro-indol-2-one

(R)-(+)-1,2-diaminopropane dihydrochloride (144 mg, 0.983 mmol) wasstirred with triethylamine in 2 mL EtOH. Once homogeneous Example 188(40 mg, 0.0983 mmol) was added and the reaction was heated at 130° C. inmicrowave for 10 min. The resulting reaction mixture was concentratedonto silica gel and flash columned (10% MeOH/1% NH₄OH in CH₂Cl₂). Theresulting fractions were concentrated to afford 13 mg (30%) of a yellowsolid. mp 247-250° C.; MS (ES⁺ calculated: 444.34; found:444.65,445.76M+H). HPLC (100%) purity, retention time 11.643 minutes—Method B);¹H NMR (400 MHz, TFA) δ 8.74 (s, 1H), 7.90 (s, 1H), 7.56 (d, J=8 Hz,1H), 7.17 (d, J=8 Hz, 1H), 4.44 (m, 2H), 4.23 (br s, 1H), 4.12 (br s,2H), 2.12 (m, 2H), 1.72 (m, 3H), 1.13 (t, J=7 Hz, 3H).

The following Examples 270-379 in Table 6 were prepared according toprocedures disclosed herein including using methods generally known toone skilled in the art.

TABLE 6

Example # R² X 370 Br —NH—(CH₂)₂—N(CH₃)₂ 371 Br —NH—(CH₂)₃—N(CH₃)₂ 372Br —(S)—NH—CH₂—CH(OH)CH₃ 373 Br —(R)—NH—CH₂—CH(OH)CH₃ 374 Cl—(S)—NH—CH₂—CH(OH)CH₃ 375 Cl —(R)—NH—CH₂—CH(OH)CH₃ 376 Cl—NH—(CH₂)₂—N(CH₃)₂ 377 Cl —NH—(CH₂)₃—N(CH₃)₂ 378 Br —NH—(CH₂)₂—NHCH₃*HCl379 Br —NH—(CH₂)₃—NHCH₃*HCl

Example 3705-Bromo-3-[2-cyclopentyl-6-(2-dimethylamino-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

A mixture of5-Bromo-3-(6-chloro-2-cyclopentyl-2-H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one(30 mg, 0.07 mmol) (Example 182), N,N-dimethylethylenediamine (61 mg,0.7 mmol) and ethanol (2 mL) were heated to 130° C. in a microwave for10 minutes. The reaction was concentrated, treated with ethyl ether andfiltered to give 15 mg (44%) of Example 370. Example 370: ¹HNMR (400MHz, TFA-d) δ 8.8 (s, 1H), 8.0 (s, 1H), 7.6 (d, 1H), 7.3 (d, 1H), 5.1(m, 1H), 4.4 (m, 2H), 4.0 (m, 3H), 3.3-3.4 (m, 6H), 2.0-2.7 (m, 8H); MS(m/e) 484 (M+1); HPLC (87%) purity, retention time 3.052 minutes—MethodC; mp 190-192° C.

Example 3715-Bromo-3-[2-cyclopentyl-6-(3-dimethylamino-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 371 was synthesized in a similar manner to Example 370 using theappropriate starting materials. Example 371: ¹HNMR (400 MHz, TFA-d) δ8.9 (s, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.4 (d, 1H), 5.2 (m, 1H), 4.1 (m,2H), 3.7-3.8 (m, 5H), 3.3 (m, 6H), 2.1-2.8 (m, 8H); MS (m/e) 498 (M+1);HPLC (90%) purity, retention time 3.042 minutes—Method C; mp 198-200° C.

Example 3725-Bromo-3-[2-cyclopentyl-64(S)-2-hydroxy-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 372 was synthesized in a similar manner to Example 370 using theappropriate starting materials. Example 372: ¹HNMR (400 MHz, TFA-d) δ8.8 (s, 1H), 8.0 (s, 1H), 7.6 (m, 1H), 7.3 (m, 1H), 5.1 (m, 1H), 4.4 (m,1H), 3.9 (m, 1H), 3.8 (m, 1H), 2.0-2.7 (m, 8H), 1.6 (d, 3H); MS (m/e)471 (M+1); HPLC (99%) purity, retention time 3.237 minutes—Method C;mp>300° C.

Example 3735-Bromo-3-[2-cyclopentyl-64(R)-2-hydroxy-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 373 was synthesized in a similar manner to Example 370 using theappropriate starting materials. Example 373: ¹HNMR (400 MHz, TFA-d) δ8.8 (s, 1H), 8.0 (s, 1H), 7.6 (m, 1H), 7.3 (m, 1H), 5.1 (m, 1H), 4.4 (m,1H), 3.9 (m, 1H), 3.8 (m, 1H), 2.0-2.7 (m, 8H), 1.6 (d, 3H); MS (m/e)471 (M+1); HPLC (99%) purity, retention time 3.238 minutes—Method C;mp>300° C.

Example 3745-Chloro-3-[2-cyclopentyl-64(S)-2-hydroxy-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 374 was synthesized in a similar manner to Example 370 usingExample 113A and the appropriate starting materials. Example 374: ¹HNMR(400 MHz, TFA-d) δ 8.8 (s, 1H), 7.7 (s, 1H), 7.3 (m, 1H), 7.2 (m, 1H),5.0 (m, 1H), 4.3 (m, 1H), 3.8 (m, 1H), 3.7 (m, 1H), 2.0-2.7 (m, 8H), 1.6(d, 3H); MS (m/e) 427 (M+1); HPLC (99%) purity, retention time 3.169minutes—Method C; mp>300° C.

Example 3755-Chloro-3-[2-cyclopentyl-64(R)-2-hydroxy-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 375 was synthesized in a similar manner to Example 370 usingExample 113A and the appropriate starting materials. Example 375: ¹HNMR(400 MHz, TFA-d) δ 8.8 (s, 1H), 7.7 (s, 1H), 7.3 (m, 1H), 7.2 (m, 1H),5.0 (m, 1H), 4.3 (m, 1H), 3.8 (m, 1H), 3.7 (m, 1H), 2.0-2.7 (m, 8H), 1.6(d, 3H); MS (m/e) 427 (M+1); HPLC (99%) purity, retention time 3.167minutes—Method C; mp>300° C.

Example 3765-Chloro-3-[2-cyclopentyl-6-(2-dimethylamino-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 376 was synthesized in a similar manner to Example 370 usingExample 113A and the appropriate starting materials. Example 376: ¹HNMR(400 MHz, TFA-d) δ 8.8 (s, 1H), 7.8 (s, 1H), 7.6 (d, 1H), 7.3 (d, 1H),5.1 (m, 1H), 4.4 (m, 2H), 4.0 (m, 3H), 3.3-3.4 (m, 6H), 2.0-2.7 (m, 8H);MS (m/e) 440 (M+1); HPLC (95%) purity, retention time 2.994minutes—Method C; mp 145-148° C.

Example 3775-Chloro-3-[2-cyclopentyl-6-(3-dimethylamino-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one

Example 377 was synthesized in a similar manner to Example 370 usingExample 113A and the appropriate starting materials. Example 377: ¹H NMR(400 MHz, TFA-d) δ 8.9 (s, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.4 (d, 1H),5.2 (m, 1H), 4.1 (m, 2H), 3.8 (m, 3H), 3.3 (m, 8H), 2.1-2.8 (m, 8H); MS(m/e) 454 (M+1); HPLC (99%) purity, retention time 2.986 minutes—MethodC; mp 176-179° C.

Example 3785-Bromo-3-[2-cyclopentyl-6-(2-methylamino-ethylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-one hydrochloride salt

A mixture of5-Bromo-3-(6-chloro-2-cyclopentyl-2-H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one(50 mg, 0.115 mmol) (Example 182), N′-BOC-N′-methylethylenediamine (200mg, 1.15 mmol) and ethanol (2 mL) were heated to 130° C. in a microwavefor 10 minutes. The reaction was concentrated, treated with ethyl etherand filtered to give 36 mg (55%) of the product. The product wasdissolved in 4N HCl in dioxane (3 mL) and stirred at rt for 1 hr. Thereaction was concentrated, treated with acetone and filtered. The solidwas washed with acetone, ethyl ether and pumped dry to give 9 mg (28%)of Example 378. Example 378: ¹H NMR (400 MHz, TFA-d) δ 8.9 (s, 1H), 8.1(s, 1H), 7.7 (d, 1H), 7.4 (d, 1H), 5.1 (m, 1H), 4.3 (m, 2H), 4.0 (m,4H), 3.1 (m, 3H), 2.1-2.8 (m, 8H); MS (m/e) 470 (M+1); HPLC (99%)purity, retention time 3.040 minutes—Method C; mp 201-204° C.

Example 3795-Bromo-3-[2-cyclopentyl-6-(3-methylamino-propylamino)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-1,3-dihydro-indol-2-onehydrochloride salt

Example 379 was synthesized in a similar manner to Example 378 using theappropriate starting materials. Example 379: ¹H NMR (400 MHz, TFA-d) δ8.9 (s, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.4 (d, 1H), 5.1 (m, 1H), 4.3 (m,2H), 3.5 (m, 8H), 2.1-2.8 (m, 8H); MS (m/e) 484 (M+1); HPLC (99%)purity, retention time 3.003 minutes—Method C; mp 208-211° C.

Scheme 9 discloses a general procedure for the preparation of compoundsof the invention wherein R⁶ is an alkyl group.

Example 3805-Bromo-3-(2-isopropyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Example 380 was synthesized in using the general procedure of Scheme 9,wherein R²=Br, and the appropriate starting materials. Example 380:¹HNMR (400 MHz, TFA-d) δ 9.1 (s, 1H), 8.8 (s, 1H), 7.9 (s, 1H), 7.6 (d,1H), 7.2 (d, 1H), 5.0 (m, 1H), 1.8 (m, 6H); MS (m/e) 373 (M+1); HPLC(99%) purity retention time 3.298 minutes—Method C; mp>300° C.

Example 3815-Chloro-3-(2-isopropyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one

Example 381 was synthesized in using the general procedure of Scheme 9,wherein R²═Cl, and the appropriate starting materials. Example 381:¹HNMR (400 MHz, TFA-d) δ 9.1 (s, 1H), 8.9 (s, 1H), 7.8 (s, 1H), 7.4 (d,1H), 7.3 (d, 1H), 5.0 (m, 1H), 1.8 (m, 6H); MS (m/e) 328 (M+1); HPLC(99%) purity retention time 3.189 minutes—Method C; mp>300° C.

Example 3823-(2-Isopropyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile

Example 382 was synthesized in using the general procedure of Scheme 9,wherein R²═CN, and the appropriate starting materials. Example 382:¹HNMR (400 MHz, TFA-d) δ 10.3 (s, 1H), 9.0 (s, 1H), 8.3 (s, 1H), 7.9 (d,1H), 7.5 (d, 1H), 5.0 (m, 1H), 1.8 (m, 6H); MS (m/e) 319 (M+1); HPLC(99%) purityretention time 3.189 minutes—Method C; mp>300° C.

Example 3835-Bromo-3-fluoro-3-(2-propyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydroindol-2-one

To a solution of Example 97 (85 mg, 0.23 mmol) in a mixture ofTHF/dioxane (1:1. 12.8 mL) was added a 1M solution of sodiumbis(trimethylsilyl)amide (0.23 ml) at −40° C. followed by addition of1-fluoro-2,4,6-trimethylpyridinium triflate (67 mg, 0.23 mmol). Thereaction was allowed to warm to room temperature where it stirredovernight. The reaction was heated to ˜50° C. for 4 h then quenched withammonium chloride. The reaction was concentrated in vacuo and purifiedprep HPLC on a Rainin Dynamax system with a Higgins Analytical Clipeus10 μm C18 column (250×20 mm). Example 383: ¹HNMR (400 MHz, DMSO-d₆) δ0.91 (s, 3H), 2.02 (m, 2H), 4.54 (m, 2H), 6.98 (d, 1H), 7.53 (s, 1H),7.61 (d, 1H), 8.85 (s, 1H), 9.03 (s, 1H), 11.2 (s, 1H); MS (m/e) 391(M+1); HPLC (91%) purity retention time 3.87 minutes—Method F; mp184-186° C.

HPLC Methods:

Wavelengths monitored included 254, 290 and/or 215 nm

-   Method A: Flow rate: 1.6 mL/min, gradient over 15 minutes from 10 to    50% [acetonitrile (0.1% TFA added):water (0.1% TFA added)] ramping    with a gradient from 50% to 100% acetonitrile:water from 15 to 20    minutes, column: 5 micron Zorbax RX-C8 (4.6×150 mm).-   Method B: Flow rate 1.6 mL/min, gradient over 20 minutes from 10 to    100% [acetonitrile (0.1% TFA added):water (0.1% TFA added)], column:    5 micron Zorbax RX-C8 (4.6×150 mm).-   Method C: Flow rate 2.4 mL/min, gradient over 8 minutes at 30° C.    from 10 to 100% [acetonitrile (0.1% TFA added):water (0.1% TFA    added)], column: 3.5 micron Zorbax SB-C18 (4.6×75 mm).-   Method D: Flow rate 1.6 mL/min, 100% water (0.1% TFA added) for 1    minute, gradient over 15 minutes from 0 to 100% [acetonitrile (0.1%    TFA added):water] 100% acetonitrile for 4 minutes, column: 5 micron    Zorbax RX-C8 (4.6×150 mm).-   Method E: Flow rate 1.6 mL/min, 10-100% Acetonitrile/water (both    with 0.1% TFA) over 7 minutes.-   Method F: Flow rate 1.6 mL/min, 10-100% Acetonitrile/water (both    with 0.1% TFA) over 8 minutes.

It is noted that NMRs of some oxindole containing products (particularlyin the N-2 series) are very complicated due to possible restrictedrotational isomerism as well as possible tautomeric forms—signalpositions only and no integrations are given for the N-2 series due toinability to assign protons.

Utility

The present invention relates to novel substituted heterobicyclicpyrimidine compounds, in particular substituted pyrazolopyrimidineoxindoles, that act as inhibitors of glycogen synthase kinase 3 and/orcyclin dependant kinase 5, and their use in the treatment of chronicneurodegenerative diseases, neurotraumatic diseases, depression and/ordiabetes. Compounds of the present invention are well suited asinhibitors of GSK-3β activity and/or CDK5 activity. Representativecompounds of the invention have exhibited good in vitro potency againstGSK-3β kinase and/or CDK5 kinase. Table 7 below provides data related toseveral example compounds of the invention with respect to, for example,ability to inhibit GSK-3β activity and/or CDK5 activity. Accordingly,the compounds of the present invention are expected to be useful in theprevention and/or treatment of conditions mediated by GSK-3β activityand/or CDK5 activity.

Cloning, Expression and Purification of CDK5/GST-p25

Two recombinant baculoviral constructs were created, one encoding forhuman CDK5 and the other encoding for human p25 with an amino-terminalglutathione-S-transferase (GST) tag. PCR amplification of full-lengthCDK5 was performed utilizing human brain cDNA as a template and PfuTurbo polymerase (Strategene). The PCR product from this reaction wassubcloned into the baculoviral expression vector pFASTBAC1 (Gibco/BRL).The final construct, encoding for full-length human CDK5 (base pairs25-903 of GenBank Accession #NM_(—)004935), is 292 amino acids long witha predicted MW of 33.3 kDa.

For p25, the active truncated form of p35, amino acids 108-307 werePCR-amplified from human fetal brain cDNA (Clontech QUICK-Clone cDNA)using the Advantage 2 PCR system (Clontech). The PCR product wassubcloned into the baculoviral transfer vector pFBGSTP (an engineeredderivative of the baculoviral transfer vector pFASTBAC1). The finalbaculoviral construct encodes for base pairs 419-1021 of GenBankAccession #NM_(—)003885, with an amino-terminal GST tag. The expressedGST-p25 is 444 amino acids long with a predicted MW of 50.3 kDa.

The CDK5/GST-p25 complex was generated by coexpression. Sf21 cells werecultured in TNM-FHS media at a density of 1.5×10⁶ cells/mL and infectedwith each recombinant virus at MOI values of 5 (for CDK5) and 10 (forGST-p25). The cells were harvested 40 h after infection. Forpurification, the 100,000×g supernatant solution was used. Expressionwas confirmed by running samples on SDS-PAGE, followed by immunoblotanalysis utilizing antibodies against CDK5 (anti-CDK5 (268-283);Calbiochem #219449) and p35 (Santa Cruz #sc820). The CDK5/GST-p25complex was purified by glutathione affinity chromatography.

Inhibition of CDK5/GST-p25 Kinase Activity

Compounds were tested for their ability to inhibit the kinase activityof recombinant baculoviral CDK5/GST-p25 using an enzyme-linkedimmunosorbent assay (ELISA) with time-resolved fluorescence (TRF)readout. Briefly, each 384-well FluoroNunc Maxisorp plate (Cat # 460372)plate was coated with 50 μl/well of 50 μg/ml substrate solution(recombinant GST-Rb(773-928)) in Tris-buffered saline (TBS). TheCDK5/GST-p25 assay mixture (total volume=50 μl/well) consisting of 20 mMHEPES (pH 7.2), 10 μM ATP, 10 mM MgCl₂, 5 mM EGTA, 25 mMβ-glycerophosphate, 0.05% BSA, 2.5% DMSO, and various concentrations oftest compound were then added to the assay plate. Enzyme (2 ng/mlCDK5/GST-p25) was added and the reaction was allowed to proceed at 37°C. for 20 minutes. Detection of the phosphorylated product was performedby adding 50 μl/well of phospho-Rb (Ser-780) antibody (Cell Signaling #9307) diluted 1:10,000 in antibody dilution buffer (0.1% BSA in TBST).After 1-hour incubation at 37° C., 50 μl/well of Eu-Nl labelledanti-rabbit antibody (Wallac # AD0105; 1:50,000 in antibody dilutionbuffer) was added. Incubation at 37° C. then proceeded for 1 hour,followed by addition of 50 μl enhancement solution (Wallac #1244-105).The plate was gently agitated and after a few minutes, the fluorescenceof the resulting solution was measured using a Multilabel Reader(Victor2 Model # 1420-018 or Envision Model # 2100). Inhibition datawere analyzed using ActivityBase and IC₅₀ curves were generated usingXLFit 3.0.5.

Cloning, Expression and Purification of His₆-GSK-3β

Full-length GSK-3β was amplified from a sequence-verified I.M.A.G.E. ESTacquired from Research Genetics (Invitrogen, Clone ID# CSODB003YJ02).The final sequence-verified cDNA contained the coding region for aNH₂-terminal tag, which encoded for 6 histidines and then eightvector-encoded amino acids prior to the start of GSK3β, which containedby # 43-1342 of Genbank Accession # NM_(—)002093, encoding amino acids#2-419. The predicted molecular weight of the tagged, 435 amino acid,full-length protein is 48.5 kDa. The major structural element of thisprotein is the kinase domain, which is from amino acids #56-340.Recombinant baculoviral DNA was prepared by transposition in E. coli(BAC-TO-BAC system: Invitrogen) and the virus generated and amplified inSf21 insect cells. A suspension culture of Sf21 cells was infected at anMOI of 0.7 and cell density of 1.5×10⁶ cells/mL in Excell 420 serum-freemedia (JRH BioScience) and harvested 65 h after infection. The 100,000×gsupernatant solution was used for purification. Expression was confirmedby running samples on SDS-PAGE, followed by immunoblot analysisutilizing both a Penta-HIS antibody (Qiagen #34660) and a GSK-3α/GSK-3βantibody (Calbiochem #368662, data not shown). The His₆-tagged proteinwas purified to in one step by Ni-NTA affinity chromatography.

Inhibition of His₆-GSK-3β Kinase Activity

Inhibitory effects of compounds on baculoviral GSK-3β kinase activitywere evaluated using an ELISA-based format in a 384-well FluoroNuncMaxisorp plate (Cat # 460372) with a time-resolved fluorescence readout.Briefly, each plate was coated with 50 μl/well of 20 μg/ml substratesolution (recombinant GST-Rb) in Tris-buffered saline (TBS). The GSK-3βassay mixture (total volume=50 μl/well) consisting of 50 mM HEPES (pH7.2), 20 μM ATP, 10 mM MgCl₂, 5 mM EGTA, 25 mM β-glycerophosphate, 0.05%BSA, 2.5% DMSO, and various concentrations of test compound were thenadded to the assay plate. Enzyme (200 ng/ml His₆-GSK-3β) was then addedand the reaction was allowed to proceed at 37° C. for 30 minutes.Detection of the phosphorylated product was performed by adding 50μl/well of phospho-Rb (Ser-780) antibody (Cell Signaling # 9307) diluted1:10,000 in antibody dilution buffer (0.1% BSA in TBST). After 1-hourincubation at 37° C., 50 μl/well of Eu-N1 labelled anti-rabbit antibody(Wallac # AD0105; 1:50,000 in antibody dilution buffer) was added.Incubation at 37° C. then proceeded for 1 hour, followed by addition of50 μl enhancement solution (Wallac #1244-105). The plate was gentlyagitated and after a few minutes, the fluorescence of the resultingsolution was measured using a Multilabel Reader (Victor2 Model #1420-018 or Envision Model 2100). Inhibition data were analyzed usingActivityBase and IC₅₀ curves were generated using XLFit 3.0.5.

Compound Activity

Using the assays disclosed herein the following Table 7 demonstrates theutility of compounds of the invention for tau kinase inhibition.Compounds of the present invention are considered active if their IC₅₀values are less than 50 uM. In the following Table, for the inhibitionof CDK5, compounds of the present invention with a “+” are less than10000 nM; compounds of the present invention with a “++” are less than3000 nM; and compounds of the present invention with a “+++” are lessthan 300 nM in IC₅₀ for CDK5 inhibition. In the following Table, for theinhibition of GSK3β, compounds of the present invention with a “+” areless than 10000 nM; compounds of the present invention with a “++” areless than 3000 nM; and compounds of the present invention with a “+++”are less than 300 nM in IC₅₀ for GSK3β inhibition. Where “>+” occursactivity was greater than the limits of the assay. Where no IC₅₀ valueis represented, data has yet to be determined.

TABLE 7 Example CDK5 IC₅₀ (nM) GSK3β IC₅₀ (nM) 30 +++ +++ 31 +++ +++ 32++ >3000 33 +++ +++ 34 +++ +++ 35 >3000 ++ 36 +++ +++ 37 ++ ++ 38 >+ >+39 +++ ++ 40 +++ ++ 41 ++ ++ 42 ++ ++ 43 ++ ++ 44 >+ >+ 45 +++ +++ 46+++ +++ 47 ++ ++ 48 ++ +++ 49 +++ +++ 50 ++ ++ 51 >3000 52 ++ ++ 53 >+++ 54 >3000 >+ 55 >+ ++ 56 >+ >+ 57 >+ ++ 58 >+ >3000 59 >+ ++ 60 >+ >+61 >+ >+ 62 >+ >3000 63 >+ ++ 64 >+ >+ 65 >+ >+ 66 >+ >3000 67 >+ >+68 >+ >+ 69 >3000 >+ 70 >+ >+ 71 >+ >+ 72 >+ >+ 73 >+ >+ 74 >+ >+75 >+ >+ 76 +++ ++ 82 +++ ++ 83 +++ ++ 84 +++ ++ 85 +++ >3000 86 +++ >+89 +++ +++ 90 +++ ++ 93 >+ >+ 94 >+ >+ 95 >3000 >+ 96 +++ +++ 97 +++ +++98 +++ +++ 99 +++ 62% @10 μM 100 +++ ++ 108 +++ >+ 109 +++ +++ 111 ++++++ 113 >+ +++ 114 +++ +++ 115 +++ +++ 116 +++ 117 + +++ 118 ++ +++ 119++ +++ 120 >+ +++ 121 >+ +++ 122 >+ +++ 123 +++ +++ 124 ++ +++ 125 >++++ 126 +++ +++ 127 >+ +++ 128 >+ +++ 129 >+ +++ 130 >+ +++ 131 >+ +++132 >+ +++ 133 +++ +++ 134 >3000 +++ 135 >+ +++ 136 >3000 +++ 137 >+ +++138 ++ +++ 139 +++ +++ 140 >+ +++ 141 >+ +++ 142 143 >+ +++ 144 >+ +++148 >+ >+ 149 +++ +++ 150 76% @10 μM +++ 151 +++ +++ 152 >+ >+153 >+ >3000 154 68% @10 μM ++ 155 >1000 ++ 156 +++ +++ 157 >3000 ++158 >3000 ++ 159 >+ >+ 160 >+ +++ 161 68% @10 μM +++ 162 >1000 +++ 163++ +++ 164 >+ +++ 165 +++ +++ 166 41% @10 μM +++ 167 >3000 +++ 168 ++++++ 169 >+ +++ 170 ++ +++ 171 +++ +++ 172 >+ +++ 173 +++ +++ 174 +++ +++175 +++ +++ 176 +++ +++ 177 +++ +++ 178 ++ +++ 179 ++ +++ 180 +++ +++181 70% @10 μM +++ 182 >+ >3000 183 184 +++ +++ 185 +++ +++ 186 +++ +++187 +++ +++ 188 >+ >3000 189 +++ +++ 190 +++ +++ 191 +++ +++ 192 +++ +++193 +++ +++ 194 +++ +++ 195 +++ +++ 196 +++ +++ 197 +++ +++ 198 +++ +++199 +++ +++ 200 +++ +++ 201 +++ +++ 202 +++ +++ 203 +++ +++ 204 ++ >3000205 >3000 >+ 211 >+ >+ 212 +++ +++ 213 +++ +++ 214 +++ +++ 215 ++ ++ 216++ ++ 217 +++ +++ 218 +++ +++ 219 +++ +++ 225 >+ +++ 226 +++ +++ 227 ++++++ 228 +++ +++ 229 ++ ++ 230 +++ +++ 231 +++ +++ 232 +++ +++ 233 ++++++ 234 +++ +++ 235 +++ +++ 236 >+ >+ 237 +++ +++ 238 +++ +++ 239 ++++++ 240 +++ +++ 241 ++ +++ 242 43% @10 μM ++ 243 63% @10 μM >1000244 >+ >1000 245 >+ >3000 246 >3000 +++ 247 >+ +++ 248 >+ +++ 249 >+ 52%@10 μM 250 >+ +++ 251 >3000 +++ 252 ++ +++ 253 ++ +++ 254 ++ +++261 >+ >3000 262 >+ >3000 263 +++ +++ 264 +++ +++ 265 +++ +++ 267 ++++++ 268 +++ +++ 269 +++ +++ 270 ++ +++ 271 +++ +++ 272 +++ +++273 >+ >3000 275 >+ +++ 276 ++ +++ 277 +++ +++ 278 ++ +++ 279 ++ +++280 >+ +++ 287 288 ++ +++ 289 +++ +++ 290 73% @10 μM +++ 291 >3000 ++292 +++ +++ 293 +++ +++ 294 73% @10 μM 70% @10 μM 295 +++ +++ 300 301+++ +++ 302 +++ +++ 303 +++ ++ 304 +++ +++ 305 +++ +++ 306 +++ ++ 307 ++++ 309 ++ ++ 310 ++ ++ 314 >+ >+ 315 >+ >+ 316 >+ >+ 317 >+ >+ 318 >+ >+319 >+ >+ 320 >3000 >3000 321 >3000 >3000 322 >3000 >+ 323 >+ >+324 >3000 >3000 325 >+ >+ 326 >+ ++ 327 >3000 ++ 328 >+ >+ 329 >+ >+330 >+ >+ 331 >+ ++ 332 >3000 ++ 333 >+ >+ 334 >+ >+ 335 >3000 >3000336 >+ >3000 337 ++ ++ 338 >3000 >+ 339 >+ >+ 340 ++ ++ 341 ++ ++ 342 ++++ 343 >+ >+ 344 ++ 69% @10 μM 345 >+ 67% @10 μM 346 ++ ++ 347 ++ ++ 348+++ ++ 349 +++ ++ 350 >3000 ++ 351 >+ >+ 352 >+ >+ 353 >+ ++ 354 +++ ++357 358 +++ +++ 359 ++ ++ 360 ++ ++ 361 >3000 +++ 362 >3000 ++ 363 ++ ++364 +++ +++ 365 ++ +++ 366 +++ +++ 367 +++ +++ 368 +++ +++ 369 ++ +++370 >3000 +++ 371 >3000 +++ 372 77% @10 μM +++ 373 67% @10 μM +++ 37456% @10 μM +++ 375 62% @10 μM +++ 376 >+ ++ 377 >+ ++ 378 >3000 ++379 >3000 +++ 380 381 +++ ++ 382 +++ ++

Accordingly, these results demonstrate that compounds of the presentinvention exhibit inhibitory activity against GSK3β kinase and/or CDK5kinase.

References

-   1. Bacon, Edward R.; Singh, Baldev; Lesher, George Y.    6-(heterocyclyl)pyrazolo[3,4-d]pyrimidin-4-one phosphodiesterase    inhibitors. (1994), U.S. Pat. No. 5,294,612 A.-   2. Herling, Andreas; Maguire, Martin P.; Spada, Alfred P.; Myers,    Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; Ewing,    William R. Adenosine analogues for the treatment of insulin    resistance syndrome and diabetes. (2001), Ep Appl. 1 258 247 A1-   3. Chu, I. Lynch, B.M. Synthesis and Biological evaluation of    Xanthine Oxidase Inhibitors. Pyrazolo[3,4-d]pyrimidines and    Pyrazolo[3,4-b]pyridines. J Med. Chem. 1975, 18, 161-165.    Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of Formula (I) can beadministered in the form of pharmaceutical compositions. Thesecompositions can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular, andintranasal, and can be prepared in a manner well known in thepharmaceutical art.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of Formula (I)above in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like.

In therapeutic applications, compositions can be administered to apatient already suffering from a disease in an amount sufficient to cureor at least partially arrest the symptoms of the disease and itscomplications. An amount adequate to accomplish this is referred to as“therapeutically effective amount.” Effective doses will depend on thedisease condition being treated as well as by the judgement of theattending clinician depending upon factors such as the severity of thedisease, the age, weight and general condition of the patient, and thelike.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of inflammatory diseases, whichcomprise one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula(I). Such kits can further include, if desired, one or more of variousconventional pharmaceutical kit components, such as, for example,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference cited in the presentapplication, including patents, published patent applications, andjournal articles, is incorporated herein by reference in its entirety.

As those skilled in the art will appreciate, numerous changes andmodifications may be made to the embodiments of the invention withoutdeparting from the spirit of the invention. It is intended that all suchvariations fall within the scope of the invention.

1. A compound of Formula (I):

or a stereoisomeric form, a mixture of stereoisomeric forms, atautomeric form, or a pharmaceutically acceptable salt form thereof,wherein: W is CH or N; ring A is

R¹, R², R³, and R⁴ at each occurrence are independently selected from H,halo, —OR¹¹, —NO₂, —CN, —CF₃, —CHF₂, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄haloalkyl, —NR¹³R¹⁴, —NHOR^(13a), —C(═O)R¹⁵, —C(═O)OR¹⁵, —OC(═O)R¹⁵,—C(═O)NR¹³R¹⁴, —NR^(13a)C(═O)R¹⁵, —NR^(13a)CO₂R¹⁵, —OC(═O)NR¹³R¹⁴,—NR^(13a)C(═S)R¹⁵, —SR¹⁵, —S(═O)R¹⁵, —S(═O)₂R¹⁵, —S(═O)₂NR¹³R¹⁴, andC₁-C₄ alkyl substituted with 0-1 R¹⁹; R⁵ is H or C₁-C₆ alkyl; R⁶ isselected from H; C₁-C₆ alkyl substituted by 0-2 R²²; C₂-C₆ alkenylsubstituted by 0-2 R²²; C₂-C₆ alkynyl substituted by 0-2 R²²; and C₃-C₇cycloalkyl substituted by 0-3 R²²; X is selected from H, —NR⁹R¹⁰, halo,OR¹², —NO₂, —CN, —CF₃, —CHF₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,C₁-C₄ haloalkyl, —CH₂NR⁹R¹⁰, —CH₂OR¹², —NHOR¹⁶, —C(═O)R¹⁸, —C(═O)OR¹⁸,—OC(═O)R¹⁸, —C(═O)NR⁹R¹⁰, —NR¹⁶C(═O)R¹⁸, —NR¹⁶CO₂R¹⁸, —OC(═O)NR⁹R¹⁰,—NR¹⁶C(═S)R¹⁸, —SR¹⁸, —S(═O)R¹⁸, —S(═O)₂R¹⁸, —S(═O)₂NR⁹R¹⁰, and—NR¹⁶S(═O)₂R¹⁸; R⁹ and R¹⁰ at each occurrence are each independentlyselected from H, —NH₂; C₁-C₆ alkyl substituted by 0-1 R¹⁹; C₂-C₆ alkenylsubstituted by 0-1 R¹⁹; C₂-C₆ alkynyl substituted by 0-1 R¹⁹; C₆-C₁₀aryl substituted by 0-5 R¹⁹; C₃-C₇ carbocyclyl substituted by 0-5 R¹⁹; 5to 14 membered heterocyclyl group substituted by 0-5 R¹⁹, wherein saidheterocyclyl group comprises one, two, or three heteroatoms selectedfrom N, O, and S; and 5 to 14 membered heteroaryl group substituted by0-5 R¹⁹, wherein said heteroaryl group comprises one, two, or threeheteroatoms selected from N, O, and S; alternatively, R⁹ and R¹⁰,together with the nitrogen to which they are attached, form a 3-7membered heterocyclic ring, wherein said 3-7 membered heterocyclic ringcontains a nitrogen atom and optionally a second atom selected from N,O, S, S(═O), and S(═O)₂, wherein said 3-7 membered heterocyclic ring issubstituted with 0-1 R¹⁷; R¹¹ at each occurrence is independentlyselected from H, C₁-C₄ alkyl, and C₁-C₄ haloalkyl; R¹² at eachoccurrence is independently selected from H, C₁-C₄ haloalkyl and C₁-C₄alkyl substituted with 0-1 R¹⁹; R¹³ and R¹⁴, at each occurrence, areindependently selected from H, C₁-C₄ alkyl substituted with 0-3 R³⁰; andC₆-C₁₀ aryl substituted with 0-5 R³⁰; R^(13a) at each occurrence isindependently selected from H, C₁-C₄ alkyl, and C₆-C₁₀ aryl; R¹⁵ at eachoccurrence is independently selected from H, C₁-C₆ alkyl substituted by0-1 R³⁰; C₂-C₆ alkenyl substituted by 0-1 R³⁰; C₂-C₆ alkynyl substitutedby 0-1 R³⁰; C₆-C₁₀ aryl substituted by 0-5 R³⁰; C₃-C₇ carbocyclylsubstituted by 0-5 R³⁰; and 5 to 14 membered heterocyclyl groupsubstituted by 0-5 R³⁰, wherein said heterocyclyl group comprises one,two, or three heteroatoms selected from N, O, and S; 5 to 14 memberedheteroaryl group substituted by 0-5 R³⁰, wherein said heteroaryl groupcomprises one, two, or three heteroatoms selected from N, O, and S; R¹⁶at each occurrence is independently selected from H and C₁-C₄ alkyl; R¹⁷is H, —NR²³R²⁴, halo, —NO₂, —CN, —CF₃, C₁-C₄ haloalkyl, —NHOH, OR²⁵,C(═O)R²⁵, C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴, NR^(23a)C(═O)R²⁵,NR^(23a)CO₂R²⁵, OC(═O)NR²³R²⁴, NR^(23a)C(═S)R²⁵, SR²⁵, S(═O)R²⁵,S(═O)₂R²⁵; S(═O)₂NR²³R²⁴, —NR^(23a)S(═O)₂R²⁵, or C₁-C₄ alkyl substitutedby 0-1 R¹⁹; R¹⁸ at each occurrence is independently selected from H;C₁-C₆ alkyl substituted by 0-1 R³⁰; C₂-C₆ alkenyl substituted by 0-1R³⁰; C₂-C₆ alkynyl substituted by 0-1 R³⁰; C₆-C₁₀ aryl substituted by0-5 R³⁰; C₃-C₇ carbocyclyl substituted by 0-5 R³⁰; and 5 to 14 memberedheterocyclyl group substituted by 0-5 R³⁰, wherein said heterocyclylgroup comprises one, two, or three heteroatoms selected from N, O, andS; 5 to 14 membered heteroaryl group substituted by 0-5 R³⁰, whereinsaid heteroaryl group comprises one, two, or three heteroatoms selectedfrom N, O, and S; R¹⁹ at each occurrence is independently selected fromH, —NR²³R²⁴, halo, —NO₂, —CN, —CF₃, C₁-C₄ haloalkyl, —NHOH, OR²⁵,C(═O)R²⁵, C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴, NR^(23a)C(═O)R²⁵,NR^(23a)CO₂R²⁵, OC(═O)NR²³R²⁴, NR^(23a)C(═S)R²⁵, SR²⁵, S(═O)R²⁵,S(═O)₂R²⁵; S(═O)₂NR²³R²⁴, —NR^(23a)S(═O)₂R²⁵, C₁-C₄ alkyl substituted by0-1 R³⁰; C₂-C₄ alkenyl substituted by 0-1 R³⁰; C₂-C₄ alkynyl substitutedby 0-1 R³⁰; C₆-C₁₀ aryl substituted by 0-5 R³⁰; C₃-C₇ carbocyclylsubstituted by 0-5 R³⁰; 5 to 14 membered heterocyclyl group substitutedby 0-5 R³⁰, wherein said heterocyclyl group comprises one, two, or threeheteroatoms selected from N, O, and S; and 5 to 14 membered heteroarylgroup substituted by 0-5 R³⁰, wherein said heteroaryl group comprisesone, two, or three heteroatoms selected from N, O, and S; R²² is H,—NR²³R²⁴, —N₃, halo, —NO₂, —CN, —CF₃, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₁-C₄ haloalkyl, C₃-C₇ carbocyclyl, phenyl, —NHOH, OR²⁵,—CH₂OR²⁵, C(═O)R²⁵, C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴,NR^(23a)C(═O)R²⁵, NR^(23a)CO₂R²⁵, OC(═O)NR²³R²⁴, NR^(23a)C(═S)R²⁵, SR²⁵,S(═O)R²⁵, S(═O)₂R²⁵; S(═O)₂NR²³R²⁴, or —NR^(23a)S(═O)₂R²⁵; R²³ and R²⁴at each occurrence are each independently selected from H or C₁-C₆alkyl; alternatively, R²³ and R²⁴, together with the nitrogen to whichthey are attached, form a 3-7 membered heterocyclic ring, wherein said3-7 membered heterocyclic ring contains a nitrogen atom and optionally asecond atom selected from N, O and S; wherein said 3-7 memberedheterocyclic ring is substituted with 0-1 C₁-C₄ alkyl; R^(23a) at eachoccurrence is each independently selected from H or C₁-C₄ alkyl; R²⁵ ateach occurrence is each independently selected from H or C₁-C₆ alkyl;and R³⁰ is H, F, Cl, Br, —CF₃, C₁-C₆ alkyl, and C₁-C₆ alkoxy.
 2. Thecompound of claim 1 wherein R¹, R², R³, and R⁴ at each occurrence areindependently selected from H, halo, —OR¹¹, —NO₂, —CN, and —CF₃.
 3. Thecompound of claim 1 wherein R¹, R³, and R⁴ are each H and R² is selectedfrom H, F, Cl, Br, —OCH₃, —NO₂, —CN, and —CF₃.
 4. The compound of claim1 wherein X is H, —NR⁹R¹⁰, halo, C₁-C₄ alkyl, or OR¹².
 5. The compoundof claim 1 wherein X is —NR⁹R¹⁰.
 6. The compound of claim 1 of Formula(II):

or a stereoisomeric form, a mixture of stereoisomeric forms, atautomeric form, or a pharmaceutically acceptable salt form thereof,wherein: ring A is

R¹, R², R³, and R⁴ at each occurrence are independently selected from H,halo, —OR¹¹, —NO₂, —CN, —CF₃, —CHF₂, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄haloalkyl, and C₁-C₄ alkyl; R⁵ is H or C₁-C₆ alkyl; R⁶ is selected fromH; C₁-C₆ alkyl substituted by 0-2 R²²; C₂-C₆ alkenyl substituted by 0-2R²²; C₂-C₆ alkynyl substituted by 0-2 R²²; and C₃-C₇ cycloalkylsubstituted by 0-2 R²²; X is H, —NR⁹R¹⁰, halo, OR¹², C₁-C₄ alkyl, orC₂-C₄ alkenyl; R⁹ and R¹⁰ at each occurrence are each independentlyselected from H, —NH₂; C₁-C₆ alkyl substituted by 0-1 R¹⁹; C₂-C₆ alkenylsubstituted by 0-1 R¹⁹; C₂-C₆ alkynyl substituted by 0-1 R¹⁹; C₆-C₁₀aryl substituted by 0-5 R¹⁹; C₃-C₇ carbocyclyl substituted by 0-5 R¹⁹; 5to 14 membered heterocyclyl group substituted by 0-5 R¹⁹, wherein saidheterocyclyl group comprises one, two, or three heteroatoms selectedfrom N, O, and S; and 5 to 14 membered heteroaryl group substituted by0-5 R¹⁹, wherein said heteroaryl group comprises one, two, or threeheteroatoms selected from N, O, and S; alternatively, R⁹ and R¹⁰,together with the nitrogen to which they are attached, form a 3-7membered heterocyclic ring, wherein said 3-7 membered heterocyclic ringcontains a nitrogen atom and optionally a second atom selected from N,O, S, S(═O), and S(═O)₂, wherein said 3-7 membered heterocyclic ring issubstituted with 0-1 R¹⁷; R¹¹ at each occurrence is independentlyselected from H, C₁-C₄ alkyl, and C₁-C₄ haloalkyl; R¹² at eachoccurrence is independently selected from H, C₁-C₄ haloalkyl and C₁-C₄alkyl substituted with 0-1 R¹⁹; R¹⁷ is H or C₁-C₄ alkyl substituted by0-1 R¹⁹; R¹⁹ at each occurrence is independently selected from H,—NR²³R²⁴, halo, —NO₂, —CN, —CF₃, C₁-C₄ haloalkyl, —NHOH, OR²⁵, C(═O)R²⁵,C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴, NR^(23a)C(═O)R²⁵, NR^(23a)CO₂R²⁵,OC(═O)NR²³R²⁴, NR^(23a)C(═S)R²⁵, SR²⁵, S(═O)R²⁵, S(═O)₂R²⁵;S(═O)₂NR²³R²⁴, —NR^(23a)S(═O)₂R²⁵, C₁-C₄ alkyl substituted by 0-1 R³⁰;C₂-C₄ alkenyl substituted by 0-1 R³⁰; C₂-C₄ alkynyl substituted by 0-1R³⁰; C₆-C₁₀ aryl substituted by 0-5 R³⁰; C₃-C₇ carbocyclyl substitutedby 0-5 R³⁰; 5 to 14 membered heterocyclyl group substituted by 0-5 R³⁰,wherein said heterocyclyl group comprises one, two, or three heteroatomsselected from N, O, and S; and 5 to 14 membered heteroaryl groupsubstituted by 0-5 R³⁰, wherein said heteroaryl group comprises one,two, or three heteroatoms selected from N, O, and S; R²² is H, —NR²³R²⁴,—N₃, halo, —NO₂, —CN, —CF₃, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl,C₁-C₄ haloalkyl, C₃-C₇ carbocyclyl, phenyl, —NHOH, OR²⁵, —CH₂OR²⁵,C(═O)R²⁵, C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴, NR^(23a)C(═O)R²⁵,NR^(23a)CO₂R²⁵, OC(═O)NR²³R²⁴, NR^(23a)C(═S)R²⁵, SR²⁵, S(═O)R²⁵,S(═O)₂R²⁵; S(═O)₂NR²³R²⁴, or —NR^(23a)S(═O)₂R²⁵; R²³ and R²⁴ at eachoccurrence are each independently selected from H or C₁-C₆ alkyl;alternatively, R²³ and R²⁴, together with the nitrogen to which they areattached, form a 3-7 membered heterocyclic ring, wherein said 3-7membered heterocyclic ring contains a nitrogen atom and optionally asecond atom selected from N, O and S, wherein said 3-7 memberedheterocyclic ring is substituted with 0-1 C₁-C₄ alkyl; R^(23a) at eachoccurrence is each independently selected from H or C₁-C₄ alkyl; R²⁵ ateach occurrence is each independently selected from H or C₁-C₆ alkyl;and R³⁰ is H, F, Cl, Br, —CF₃, C₁-C₆ alkyl, and C₁-C₆ alkoxy.
 7. Thecompound of claim 6 wherein R¹, R², R³, and R⁴ at each occurrence areindependently selected from H, F, Cl, Br, —OCH₃, —NO₂, —CN, and —CF₃. 8.The compound of claim 6 wherein R¹, R³, and R⁴ are each H and R² isselected from H, F, Cl, Br, —OCH₃, —NO₂, —CN, and —CF₃.
 9. The compoundof claim 6 wherein X is —NR⁹R¹⁰.
 10. The compound of claim 6 wherein R⁶is cyclopentyl.
 11. The compound of claim 1 of Formula (III):

or a stereoisomeric form, a mixture of stereoisomeric forms, atautomeric form, or a pharmaceutically acceptable salt form thereof,wherein: ring A is

R² is selected from H, halo, —OR¹¹, —NO₂, —CN, —CF₃, —CHF₂, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₁-C₄ haloalkyl, and C₁-C₄ alkyl; R⁵ is H ormethyl; R⁶ is selected from H; C₁-C₆ alkyl substituted by 0-2 R²²; C₂-C₆alkenyl substituted by 0-2 R²²; C₂-C₆ alkynyl substituted by 0-2 R²²;and C₃-C₇ cycloalkyl substituted by 0-2 R²²; X is H, —NR⁹R¹⁰, halo,OR¹², C₁-C₄ alkyl, or C₂-C₄ alkenyl; R⁹ and R¹⁰ at each occurrence areeach independently selected from H, —NH₂; C₁-C₆ alkyl substituted by 0-1R¹⁹; C₂-C₆ alkenyl substituted by 0-1 R¹⁹; C₂-C₆ alkynyl substituted by0-1 R¹⁹; C₆-C₁₀ aryl substituted by 0-5 R¹⁹; C₃-C₇ carbocyclylsubstituted by 0-51e; 5 to 14 membered heterocyclyl group substituted by0-5, wherein said heterocyclyl group comprises one, two, or threeheteroatoms selected from N, O, and S; and 5 to 14 membered heteroarylgroup substituted by 0-5 R¹⁹, wherein said heteroaryl group comprisesone, two, or three heteroatoms selected from N, O, and S; alternatively,R⁹ and R¹⁰, together with the nitrogen to which they are attached, forma 3-7 membered heterocyclic ring, wherein said 3-7 membered heterocyclicring contains a nitrogen atom and optionally a second atom selected fromN, O, S, S(═O), and S(═O)₂, wherein said 3-7 membered heterocyclic ringis substituted with 0-1 R¹⁷; R¹¹ at each occurrence is independentlyselected from H, C₁-C₄ alkyl, and C₁-C₄ haloalkyl; R¹² at eachoccurrence is independently selected from H, C₁-C₄ haloalkyl and C₁-C₄alkyl substituted with 0-1 R¹⁹; R¹⁷ is H or C₁-C₄ alkyl substituted by0-1 R¹⁹; R¹⁹ at each occurrence is independently selected from H,—NR²³R²⁴, halo, —NO₂, —CN, —CF₃, C₁-C₄ haloalkyl, —NHOH, OR²⁵, C(═O)R²⁵,C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴, NHC(═O)R²⁵, NHCO₂R²⁵, OC(═O)NR²³R²⁴,NHC(═S)R²⁵, SR²⁵, S(═O)R²⁵, S(═O)₂R²⁵; S(═O)₂NR²³R²⁴, —NHS(═O)₂R²⁵,C₁-C₄ alkyl substituted by 0-1 R³⁰; C₂-C₄ alkenyl substituted by 0-1R³⁰; C₂-C₄ alkynyl substituted by 0-1 R³⁰; C₆-C₁₀ aryl substituted by0-5 R³⁰; C₃-C₇ carbocyclyl substituted by 0-5 R³⁰; 5 to 14 memberedheterocyclyl group substituted by 0-5 R³⁰, wherein said heterocyclylgroup comprises one, two, or three heteroatoms selected from N, O, andS; and 5 to 14 membered heteroaryl group substituted by 0-5 R³⁰, whereinsaid heteroaryl group comprises one, two, or three heteroatoms selectedfrom N, O, and S; R²² is H, —NR²³R²⁴, —N₃, halo, —NO₂, —CN, —CF₃, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ haloalkyl, C₃-C₇ carbocyclyl,phenyl, —NHOH, OR²⁵, C(═O)R²⁵, C(═O)OR²⁵, OC(═O)R²⁵, C(═O)NR²³R²⁴,NHC(═O)R²⁵, NHCO₂R²⁵, OC(═O)NR²³R²⁴, NHC(═S)R²⁵, SR²⁵, S(═O)R²⁵,S(═O)₂R²⁵; S(═O)₂NR²³R²⁴, or —NHS(═O)₂R²⁵; R²³ and R²⁴ at eachoccurrence are each independently selected from H or C₁-C₄ alkyl; R²⁵ ateach occurrence is each independently selected from H or C₁-C₄ alkyl;and R³⁰ is H, F, Cl, Br, —CF₃, C₁-C₄ alkyl, and C₁-C₄ alkoxy.
 12. Thecompound of claim 11 wherein R⁶ is cyclobutyl, cyclopentyl, orcyclohexyl.
 13. The compound of claim 11 wherein R⁶ is cyclopentyl. 14.The compound of claim 11 wherein X is —NR⁹R¹⁰.
 15. The compound of claim11 wherein R⁶ is cyclopentyl and X is —NR⁹R¹⁰.
 16. The compound of claim1 of Formula (II)

or a stereoisomeric form, a mixture of stereoisomeric forms, atautomeric form, or a pharmaceutically acceptable salt form thereof,wherein: ring A is

R¹, R², R³, and R⁴ at each occurrence are independently selected from H,F, Cl, Br, —OCH₃, —NO₂, —CN, and —CF₃; R⁵ is H; R⁶ is selected from H,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-pentyl, i-pentyl,allyl, cyclopentyl, cyclohexyl, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₃,—CH₂CH₂CH₂N₃, and —CH₂CH₂CH₂NHCH₃; X is selected from H, Cl, methyl,ethyl, propyl, butyl, —OH; —OCH₂CH₂N(CH₃)₂; —OCH₂CH₂(pyrid-3-yl);—NHCH₃; —NHCH₂CH₃; —NHCH(CH₃)₂; —NHCH₂CH₂CH₂CH₃; —NHCH₂CH(CH₃)₂;—NHCH₂CH₂CF₃; —NHCH═CH₂; —NHCH₂CH═CH₂; —NHCH₂CH₂N(CH₃)₂;—N(CH₃)CH₂CH₂N(CH₃)₂; —NHCH₂CH₂CH₂N(CH₃)₂; —NHCH₂CH₂CH₂NH(CH₃);—NHCH₂CH₂NH₂; —NHCH₂CH₂CH₂NH₂; —N(H)CH₂CH(NH₂)CH₃;—N(CH₃)CH₂CH₂N(CH₂CH₃)₂; —NHNH₂; —NHCH₂CH₂NHC(═O)CH₃; —N(CH₂CH₂OCH₃)₂;—N(H)CH₂CH₂OCH₃; —N(H)CH₂CH₂CH₂OCH₃; —N(H)CH₂CH₂OCH₂CH₃;—N(H)CH₂CH₂OCH₂CH₂CH₃; —N(CH₂CH₂OH)₂; —N(H)CH₂CH(OH)CH₃;—N(H)CH₂CH(OH)CH₂CH₃; —NH(pyrid-3-yl); —NH(4-F-pyrid-3-yl);—NH(4-MeO-pyrid-3-yl); piperazin-1-yl;


17. A compound which is:5-Bromo-3-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-1,3-dihydro-indol-2-one;3-(2-Chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-5-fluoro-1,3-dihydro-indol-2-one;5-Chloro-3-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-1,3-dihydro-inodol-2-one;3-(2-Chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;5-Fluoro-3-[2-(2-morpholin-4-ylethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one;3-[2-(2-Ethoxy-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-5-fluoro-1,3-dihydro-indol-2-one;5-Fluoro-3-{2-[(pyridin-4-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one;5-Fluoro-3-{2-[(pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one;5-Fluoro-3-{2-[(pyridin-2-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one;5-Chloro-3-[2-(2-dimethylamino-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one;5-Chloro-3-[2-(2-morpholin-4-yl-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one;5-Chloro-3-[2-(2-ethoxy-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one;5-Chloro-3-{2-[(pyridin-4-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one;5-Chloro-3-{2-[(pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one;5-Chloro-3-{2-[(6-chloro-pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one;5-Chloro-3-{2-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one;5-Chloro-3-{2-[(pyridin-2-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one;5-Bromo-3-[2-(3-morpholin-4-yl-propylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one;5-Bromo-3-[2-(2-morpholin-4-yl-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one;5-Bromo-3-[2-(2-propoxy-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one;5-Bromo-3-[2-(2-ethoxy-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one;5-Bromo-3-[2-(3-dimethylamino-propylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-1,3-dihydro-indol-2-one;5-Bromo-3-{2-[(pyridin-4-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one;5-Bromo-3-{2-[(pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one;5-Bromo-3-{2-[(6-chloro-pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one;5-Bromo-3-{2-[(pyridin-2-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-1,3-dihydro-indol-2-one;3-[2-(3-Morpholin-4-yl-propylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;3-[2-(2-Morpholin-4-yl-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;3-[2-(3-Dimethylamino-propylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;2-Oxo-3-[2-(2-propoxy-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2,3-dihydro-1H-indole-5-carbonitrile;3-[2-(2-Ethoxy-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;2-Oxo-3-[2-(2-pyridin-4-yl-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2,3-dihydro-1H-indole-5-carbonitrile;2-Oxo-3-[2-(2-pyridin-2-yl-ethylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2,3-dihydro-1H-indole-5-carbonitrile;2-Oxo-3-{2-[(pyridin-4-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-2,3-dihydro-1H-indole-5-carbonitrile;2-Oxo-3-{2-[(pyridin-3-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-2,3-dihydro-1H-indole-5-carbonitrile;2-Oxo-3-{2-[(pyridin-2-ylmethyl)-amino]-6,7-dihydro-5H-cyclopentapyrimidin-4-yl}-2,3-dihydro-1H-indole-5-carbonitrile;2-Oxo-3-[2-(pyridin-3-ylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2,3-dihydro-1H-indole-5-carbonitrile;3-[2-(6-Fluoro-pyridin-3-ylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;3-[2-(6-Methoxy-pyridin-3-ylamino)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;3-[2-(4-Methyl-piperazin-1-yl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile;2-Oxo-3-(2-piperazin-1-yl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-2,3-dihydro-1H-indole-5-carbonitrile;or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition comprising a compound of claim 1 and one or morepharmaceutically acceptable excipients.